Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

PDE11A

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101747

Historical Background

3′,5′-cyclic nucleotides (i.e., cAMP and cGMP) are intracellular signaling molecules that regulate a vast number of physiological processes, from cell-specific gene transcription to whole animal behavior (c.f., Neves et al. 2002; Francis et al. 2010). In order for cAMP and cGMP signaling to be effective, they must be tightly controlled. Although cyclic nucleotides are expressed in nearly every tissue, they are far from ubiquitously distributed. Cyclic nucleotides are actually confined to specific subcellular microdomains by a superfamily of enzymes known as the 3′,5′-cyclic nucleotide phosphodiesterases (PDEs) (Francis et al. 2011; Edwards et al. 2012). PDEs are the only known enzymes to degrade cyclic nucleotides (Francis et al. 2011). By hydrolyzing cAMP and cGMP, PDEs not only control the total cellular content of cAMP and cGMP, they are responsible for restricting these cyclic nucleotides to their microdomains. It is this compartmentalization of cyclic nucleotides that allows a single cell to respond discretely to multiple incoming signals despite the fact that many receptor systems across the cell all couple to the cAMP and cGMP cascades. To date, there are 11 families of PDEs (PDE1-11) that are encoded by 21 genes (Bender and Beavo 2006; Francis et al. 2011). Note that “PDE12” hydrolyzes 2′,3′-cyclic nucleotides instead of 3′,5′-cyclic nucleotides. Many PDE genes are alternatively spliced, ultimately resulting in over 100 unique PDE isoforms (Bender and Beavo 2006; Francis et al. 2011). Although each tissue expresses more than one PDE isoform, no two PDE isoforms exhibit the exact same tissue expression profile and subcellular localization pattern (Bender and Beavo 2006; Kelly and Brandon 2009; Francis et al. 2011; Xu et al. 2011; Kelly et al. 2014; Lakics et al. 2010). Thus, each PDE isoform represents a unique entity regulating separable physiological processes.

The most recently discovered 3′,5′-cyclic nucleotide PDE family is PDE11, and in vitro studies suggest PDE11 hydrolyzes cAMP and cGMP equally well (Fawcett et al. 2000; Hetman et al. 2000; Yuasa et al. 2000, 2001b; Weeks et al. 2007). The PDE11 family is comprised of a single gene, PDE11A, which produces four different PDE11A isoforms (PDE11A1-4) as a result of four different transcriptional start sites in combination with alternative splicing events (Fawcett et al. 2000; Hetman et al. 2000; Yuasa et al. 2000, 2001a, b) (Fig. 1). The N-terminus of each isoform functions as a regulatory domain, while the C-terminus of each isoform contains the catalytic domain (Weeks et al. 2007). The longest isoform of PDE11A, PDE11A4, demonstrates ∼95% protein sequence homology between human, rat, and mouse. This high degree of homology suggests that insights obtained from the study of preclinical rodent models will be relevant to human PDE11A. Where in the body PDE11A isoforms are expressed is highly controversial, due in part to the use of a number of poor quality commercially available antibodies in combination with a lack of tissue-specific negative controls. As extensively reviewed elsewhere (Kelly 2015) and summarized in Table 1, PDE11A expression has been most consistently reported in pancreas (isoform undetermined), pituitary (PDE11A4), rodent spleen (PDE11A1-3), human and rat liver (possibly low levels of PDE11A4 and higher levels of another isoform), the hippocampus and amygdalohippocampal area of brain (PDE11A4), dorsal root ganglion (PDE11A4), spinal cord (PDE11A4), seminal vesicles (PDE11A3), and the salivary glands (isoform undetermined). Consistent with this tissue expression pattern, PDE11A signaling appears to regulate brain function, endocrine tumor suppression, and, possibly, immune activation and/or inflammatory processes (c.f., Kelly 2015).
PDE11A, Fig. 1

PDE11A1-4 each has a unique N-terminal domain but identical C-terminal domains. The GAF-A domain is represented by white empty rectangles, the GAF-B domain by white rectangles with horizontal lines, and the catalytic domain by white rectangles with diagonal lines. Translation initiation sites are indicated by the bent arrow and start codon (AUG). The exons included in each isoform are indicated above the schematic (boundaries as per the NCBI CCDS database). Below each isoform, short gray arrows indicate the amino acid demarcating the end of each exon, and longer black arrows indicate key residues of functional significance (i.e., confirmed phosphorylation sites, boundaries for each functional domain, the aspartate (D) required for functional effects associated with cGMP binding the GAF-A domain (Gross-Langenhoff et al. 2006), the glutamine (Q) required for substrate binding (Weeks et al. 2009), and the Mg2+ binding site). The original characterization of the genomic organization of PDE11A indicated that the catalytic domain started in exon 14; however, current NCBI Protein entries and CCDS definitions now place the start of the catalytic domain in exon 15 as shown in the figure. The original characterization of PDE11A also indicated the gene encoded a total of 23 exons and suggested PDE11A2 started with exon 5. That said, Hetman and colleagues (2000) indicated PDE11A2 as having a unique sequence at its N terminus, and the NCBI nucleotide database notes two exons start prior to the AUG start site, which falls within exon 5. The sequence of the second of those two exons matches that of exon 5; however, the first of those two exons does not match the sequence of exon 4 nor any of the other exons, suggesting it may represent an unnamed exon. Indeed, NCBI Gene (https://www.ncbi.nlm.nih.gov/gen/50940) shows PDE11A2 as starting with an exon that falls in between exons 4 and 5 that is not included in the other PDE11A isoforms. GAF – cGMP binding PDE, Anabaena adenylyl cyclase and E. coli FhlA domain

PDE11A, Table 1

PDE11A tissue expression studies published to date are highly contradictory (c.f., Kelly et al. 2015 for review) and should be interpreted with caution as only a few studies (e.g., [1-4]) included negative control tissue (e.g., knockout mouse, human tissue with truncating deletion) to validate probe/antibody signals. Species (Human H, Mouse M, Rat R), mRNA versus protein, and isoform indicated where information available

 

Signal intensity

Not detected

Negligible-weak

Moderate-strong

Adipose tissue

M protein: [3]

R mRNA: [5]

 

Bladder

H mRNA and protein: [6, 7]

M protein: [3]

H 11A1 protein: [8]

H mRNA: [9]

 

Bone marrow

H protein: [6, 7]

  

Cardiovascular system

   

Aorta

H protein: [6, 7, 10]

M protein: [11]

  

Atrium

H protein: [7]

  

Heart

H protein: [6, 7]

H mRNA: [12]

M protein: [3, 11]

H 11A4 mRNA: [7]

H 11A4 protein: [13]

H protein: [8]

R mRNA:[5]

H mRNA: [9]

R mRNA: [14]

Ventricle

H protein: [7]

  

Endocrine system

   

Adrenal gland

H protein: [6, 7]

M protein: [3, 11]

 

H protein: [8]

H mRNA: [9]

H 11A4 protein in cortex and nodules, not medulla: [1]

Pancreas

H mRNA: [7]

M protein: [3]

H protein: [6, 8]

R mRNA: [5]

H mRNA: [12]

H mRNA: [9]

R mRNA in islet cells: [5]

Pituitary gland

  

H 11A4 protein: [6, 7, 13]

Thyroid gland

H protein: [6, 7]

  

Epidermis

H protein fibroblasts: [8]

 

H protein endothelial cells: [8]

Gastrointestinal system

   

Appendix

H protein: [6] [7]

  

Esophagus

H protein: [7]

  

Large intestine (cecum, colon, rectum)

H protein: [6, 7]

M protein: [3]

H protein: [8]

 

Small intestine (duodenum, jejunum, ileum)

H protein: [6, 7]

R mRNA: [5]

Possibly M 11A4 protein: [3]

H protein: [8]

H mRNA: [9]

Stomach

H protein: [6, 7]

M protein: [3]

 

H mRNA: [9]

Immune system

   

Leukocyte

H protein: [6, 7]

  

Lymph node

H protein: [6, 7]

  

Macrophages

  

R mRNA (poststimulation): [15]

Spleen

H protein: [6, 7]

H mRNA: [9, 12]

H protein: [8]

R 11A2 mRNA: [14]

M 11A1 and 3 protein: [3]

T cells

  

M mRNA and protein: [16]

Thymus

H protein: [6, 7]

H mRNA: [12]

H mRNA: [9]

Kidney

H protein, 11A3 and 11A4 mRNA: [7]; H mRNA: [12]

M protein: [3, 11]

 

H protein: [6, 8]

H mRNA: [9]

R 11A4 mRNA: [14]

Liver

M protein: [3, 11]

H 11A4 protein: [13]

H protein: [8]

H mRNA: [12]

R mRNA: [5]

H protein: [6, 7]

H mRNA: [9]

R 11A4 mRNA: [14]

Lung

H protein: [6, 7]

M protein: [3, 11]

H mRNA: [12]

R 11A3 and 11A4 mRNA: [14]

H mRNA: [9]

H protein: [8]

R 11A2 mRNA [14]

Nervous system

   

Whole brain

H protein: [6, 7]

H protein: [8]

R 11A2 and 11A4 mRNA: [14]; R mRNA: [5]

Amygdala

H protein: [6, 7]

 

M 11A4 mRNA and protein in the amygdalohippocampal area: [2, 4]

Caudate nucleus

H protein: [6, 7]

M mRNA: [2]

M protein: [11]

H mRNA: [9]

 

Cerebellum

H protein: [6, 7]

H mRNA: [9]

M mRNA and protein: [2, 11]

H mRNA: [12]

  

Cerebral cortex

H protein: [6, 7]

M mRNA: [2]

M protein: [11]

H mRNA: [9]

 

Corpus callosum

H protein: [7]

M mRNA: [2]

  

Dorsal root ganglion

 

M protein: Fig. 3a

H mRNA: [9]

Frontal lobe

H protein: [6, 7]

M mRNA: [2]

M protein: [11]

H mRNA: [9]

M and R 11A4 protein in prefrontal cortex (likely from ventral hippocampus afferents): [3, 4]

 

Hippocampus

H protein: [6, 7]

 

H mRNA: [9]

H 11A4 protein: [2]

M and R 11A4 mRNA and protein: [2, 3, 11]

Hypothalamus

M mRNA: [2]

 

H mRNA: [9]

Median eminence

  

M protein: [11]

Medulla oblongata

H protein: [6, 7]

M mRNA: [2]

 

M 11A4 protein: [11]

Nucleus accumbens

H protein: [6, 7]

M mRNA: [2, 3]

H mRNA: [9]

M and R 11A4 protein (likely from ventral hippocampus afferents): [3, 4]

 

Olfactory bulb

M mRNA: [2]

M protein: [11]

  

Occipital lobe

H protein: [6, 7]

M mRNA: [2]

  

Paracentral gyrus

H protein: [7]

M mRNA: [2]

  

Parietal lobe

H protein: [7]

H mRNA: [12]

H mRNA: [9]

 

Pons

H protein: [7]

  

Putamen

H protein: [6, 7]

M mRNA: [2]

  

Spinal cord

H protein: [6, 7]

 

H mRNA: [9]

M protein: Fig. 3a

Substantia nigra

H protein: [6, 7]

 

H mRNA: [9]

Temporal lobe

H protein: [6, 7]

M mRNA: [2]

H mRNA: [9]

 

Thalamus

H protein: [6, 7]

M mRNA: [2]

H mRNA: [9]

 

Reproductive system

   

Cervix

H protein: [7]

  

Epididymus

M protein: [3]

  

Labia minora

  

H protein: [17]

Mammary gland

 

H protein: [6, 7]

 

Ovary

H protein: [6, 7]

H mRNA: [12] (neither follicles nor granulosa cells)

H protein: [8]

Possible M 11A2 protein: [3]

Pig 11A1protein in mural granulosa cells: [18]

Penis

H protein: [13]

 

H 11A4 protein in corpus cavernosum: [8]

Placenta

H protein: [6, 7]

  

Prostate

H 11A2-4 protein: [6]

H 11A3 protein: [7]

H 11A1-3 protein: [13]

H 11A2-3 protein: [1]

M 11A4 protein: [11]

H mRNA: [12]

H 11A1 protein: [1, 6]

H 11A3 protein: [8]

H 11A4 protein: [1, 7, 13]

M 11A1 protein: [3]

R 11A2 mRNA: [14]

Seminal vesicles

  

H 11A3 protein: [19]

M 11A3 protein: [3]

Testis

H 11A1-4 protein: [13]

M protein: [3, 11]

H 11A3 and 4 protein: [8]

M protein: [10]

H mRNA: [12]

H protein: [6, 7]

H 11A3 mRNA: [7]

H 11A1-4 mRNA: [1]

Uterus

H protein: [6, 7]

H protein: [8]

 

Salivary gland

 

H protein: [7]

H protein: [6]

Skeletal muscle

H 11A2 and 3 mRNA: [1]

H 11A1 and 4 protein: [6]

H protein: [7, 13]

M protein: [3, 11]

R 11A3 and 4: [14]

H 11A3 and 4 protein: [8]

R mRNA: [5]

H mRNA: [12]

H 11A2 and 3 protein: [6]

H 11A1 and 4 mRNA: [1]

H mRNA: [9]

R 11A2 mRNA: [14]

Trachea

H protein: [6, 7]

  

Urethra

  

H 11A1 mRNA: [20]

1. Horvath A, et al. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet. 2006;38(7):794–800.

2. Kelly MP, et al. Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes. Proc Natl Acad Sci U S A. 2010;107(18):8457–62.

3. Kelly MP. Does phosphodiesterase 11A (PDE11A) hold promise as a future therapeutic target? Curr Pharm Des. 2015;21(3):389–416.

4. Hegde S, et al. Phosphodiesterase 11A (PDE11A), enriched in ventral hippocampus neurons, is required for consolidation of social but not nonsocial memories in mice. Neuropsychopharmacology. 2016a;41:2920-31.

5. Waddleton D, et al. Phosphodiesterase 3 and 4 comprise the major cAMP metabolizing enzymes responsible for insulin secretion in INS-1 (832/13) cells and rat islets. Biochem Pharmacol. 2008;76(7):884–93.

6. Fawcett L, et al. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci U S A. 2000;97(7):3702–7.

7. Yuasa K, et al. Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. J Biol Chem. 2000;275(40):31469–79.

8. D’Andrea MR, et al. Expression of PDE11A in normal and malignant human tissues. J Histochem Cytochem. 2005;53(7):895–903.

9. Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology. 2010;59(6):367–74.

10. Wayman C, et al. Phosphodiesterase 11 (PDE11) regulation of spermatozoa physiology. Int J Impot Res. 2005;17(3):216–23.

11. Jager R, et al. Activation of PDE10 and PDE11 phosphodiesterases. J Biol Chem. 2012;287(2):1210–9.

12. Petersen TS, et al. Distribution and function of 3′,5′-Cyclic-AMP phosphodiesterases in the human ovary. Mol Cell Endocrinol. 2015;403:10–20.

13. Loughney K, Taylor J, Florio VA. 3′,5′-cyclic nucleotide phosphodiesterase 11A: localization in human tissues. Int J Impot Res. 2005;17(4):320–5.

14. Yuasa K, et al. Identification of rat cyclic nucleotide phosphodiesterase 11A (PDE11A): comparison of rat and human PDE11A splicing variants. Eur J Biochem. 2001;268(16):4440–8.

15. Witwicka H, et al. Expression and activity of cGMP-dependent phosphodiesterases is up-regulated by lipopolysaccharide (LPS) in rat peritoneal macrophages. Biochim Biophys Acta. 2007;1773(2):209–18.

16. Bazhin AV, et al. Distinct metabolism of cyclic adenosine monophosphate in regulatory and helper CD4+ T cells. Mol Immunol. 2010;47(4):678–84.

17. Uckert S, et al. Immunohistochemical description of cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human labia minora. J Sex Med. 2007;4(3):602–8.

18. Bergeron A, et al. Active 3′-5′ cyclic nucleotide phosphodiesterases are present in detergent-resistant membranes of mural granulosa cells. Reprod Fertil Dev. 2016.

19. Uckert S, et al. Expression and distribution of phosphodiesterase isoenzymes in the human seminal vesicles. J Sex Med. 2011;8(11):3058–65.

20. Kedia GT, et al. Phosphodiesterase isoenzymes in the human urethra: a molecular biology and functional study. Eur J Pharmacol. 2014;741:330–5.

Genomic and Biochemical Features of PDE11A

PDE11A yields four splice variants. The PDE11A gene resides on chromosome 2 in both mouse and human (2q31.2). PDE11A was originally reported to encompass 23 exons that produce four known splice variants: PDE11A1 (but see Fig. 1) through 4 (Fawcett et al. 2000; Hetman et al. 2000; Yuasa et al. 2000, 2001a, b) (Fig. 1). There is no true “full length” PDE11A, as no isoform includes all 23 exons (Fig. 1). A phylogenetic analysis of either the catalytic domain alone (Yuasa et al. 2001a) or the longest isoform for each human PDE gene (Kelly 2015) shows that PDE11A demonstrates a high degree of sequence similarity with the other GAF-domain (see below) containing PDEs: PDE2A, PDE5A, PDE6A-C, and PDE10A. As reviewed elsewhere (Kelly 2015), each PDE11A isoform is driven by a unique promoter with distinct transcriptional elements (Yuasa et al. 2001a) likely accounting for the fact that each PDE11A isoform shows a differential tissue expression profile (Kelly 2015) (Table 1). In addition to each isoform having a unique transcription start site, there are alternative splicing events that differentiate each isoform (Fig. 1), ultimately providing each isoform with a unique N-terminal regulatory domain (Yuasa et al. 2001a).

The N-terminus regulates PDE11A function. Each PDE11A isoform has a unique N-terminal regulatory domain, containing some or all of the regulatory elements (Fig. 1). Comparing the substrate affinity of the four PDE11A isoforms shows that substrate affinity correlates negatively with the length of the N-terminus: PDE11A4 has the lowest affinity and PDE11A1 and PDE11A2 have the highest affinities for cAMP and cGMP (Weeks et al. 2007). Similarly, when the first 196 amino acids are deleted from a chimeric protein consisting of the PDE11A4 N-terminus linked to the catalytic domain of a bacterial adenylyl cyclase, increased basal catalytic activity is observed (Gross-Langenhoff et al. 2008). As discussed below, intramolecular signals within the N-terminal that appear to regulate PDE11A function include phosphorylation events, binding of cGMP to the GAF-A (cGMP binding PDE, Anabaena adenylyl cyclase and E. coli FhlA domain) domain, and homodimerization via the GAF-B domain.

The N-terminus of PDE11A4 has three confirmed phosphorylation sites. Many PDE11A residues are predicted to be phosphorylated by numerous kinases (Kelly 2015); however, only three phosphorylation sites have been proven to date (Yuasa et al. 2000; Capell et al. in preparation). PDE11A4 is the only isoform to include exon 3 (Fig. 1), which includes the three confirmed phosphorylation sites (Yuasa et al. 2000; Capell et al. in preparation). In vitro phosphorylation assays show that both PKA and PKG phosphorylate PDE11A4 but not PDE11A3 and that the majority of PKA- and PKG-induced phosphorylation of PDE11A4 is ablated when S117 and S162 are mutated to phosphomutant alanines (Yuasa et al. 2000). Phosphorylation of S124 likely accounts for the remaining PKA- and PKG-induced phosphorylation observed in the S117A/S162A phosphomutants (Kelly 2015; Capell et al. in preparation). PKG appears to phosphorylate PDE11A4 to a lesser extent than PKA, suggesting PKG may be less efficient or phosphorylate fewer residues than PKA (Yuasa et al. 2000). Importantly, S117, S124, and S162 are phosphorylated in vivo in brain tissue (Capell et al. in preparation).

The functional consequences of S117, S124, and S162 phosphorylation events are beginning to emerge. In studies using a chimeric protein consisting of the PDE11A4 N-terminus linked to the catalytic domain of a bacterial adenylyl cyclase, phosphomimic mutation of S117 and S162 increases the affinity of the GAF-A regulatory domain for cGMP (Gross-Langenhoff et al. 2008). Interestingly, the affinity of the GAF-A domain for cGMP is similarly increased after deleting the first 176 amino acids (Gross-Langenhoff et al. 2008), suggesting that the cyclic nucleotide binding pocket of the GAF-A domain is exposed (e.g., via a conformational change) following phosphorylation of S117/S162.

In two heterologous cell lines (COS-1 and HEK293T), phosphomimic mutation of S117, S124, or S162 (S117D, S124D, S162D) changes the subcellular compartmentalization of PDE11A4 (Capell et al. in preparation). Whereas S117D/S124D shifts PDE11A4 into punctate organelles and from the cytosol to the membrane relative to wild-type (WT) PDE11A4, S162D has the completely opposite effect preventing localization of PDE11A4 within punctate organelles and shifting PDE11A4 from the membrane to the cytosol (Capell et al. in preparation). Further, S162D completely blocks the effect of S117D/S124D (Capell et al. in preparation). Consistent with these results, we find that WT PDE11A4 phosphorylated at S162 is found exclusively in the cytosol; whereas, WT PDE11A4 phosphorylated at S117 and S124 can be found in both the cytosol and the membrane (Capell et al. in preparation). The fact that S162D completely blocks the effects of S117D/S124D on subcellular compartmentalization of PDE11A4 stands in contrast to the fact that S162D potentiates the effect of S117D in the context of the chimeric protein described above. Such dichotomous results obtained using a full-length PDE11A4 protein versus a chimeric protein suggest a complex interaction between these N-terminal phosphorylation events and the C-terminus.

The PDE11A GAF-A domain binds cGMP. Several laboratories have shown that cGMP binds the PDE11A GAF-A regulatory domain (Gross-Langenhoff et al. 2006, 2008; Matthiesen and Nielsen 2009; Jager et al. 2012). cAMP does not bind the PDE11A GAF-A domain, and neither cyclic nucleotide binds the GAF-B domain (Gross-Langenhoff et al. 2006, 2008; Matthiesen and Nielsen 2009; Jager et al. 2012). In addition to cGMP itself, select cGMP analogues can also bind the GAF-A domain, and both appear to bind the GAF-A domain with a lower Ki versus the catalytic domain (Matthiesen and Nielsen 2009). cGMP binding of the GAF-A domain of full-length PDE11A4 – native or recombinant – does not directly affect the catalytic activity of the enzyme (Matthiesen and Nielsen 2009; Jager et al. 2012). In contrast, cGMP binding to the GAF-A domain of the PDE11A4-cyclase chimeric protein described above does increase catalytic activity (Gross-Langenhoff et al. 2006, 2008), an effect that requires the aspartate within the NKFDE motif that is conserved in all mammalian PDE GAF domains (Gross-Langenhoff et al. 2006). Although mutating D355 to an alanine abolishes the effects of cGMP at the GAF-A domain, it is not clear if this effect is due to an inability of cGMP to bind the GAF-A domain or a blockade of some downstream effect (e.g., a cGMP-induced comformational change). Although cGMP itself does not appear to allosterically regulate catalytic activity of full-length PDE11A4, it does appear that the cGMP analogue Rp-8-pCPT-PET-cGMPs can increase the catalytic activity of both recombinant and native PDE11A4 (Jager et al. 2012). As discussed elsewhere (Kelly 2015), the use of Rp-8-pCPT-PET-cGMPs as a tool PDE11A4 activator is severely limited by off-target activities, but its ability to allosterically stimulate PDE11A4 function provides an important proof of concept for how to develop PDE11A4 activators.

The PDE11A GAF-B domain is required for homodimerization. GAF domains not only serve as regions for binding of cyclic nucleotides, they contribute to protein-protein binding interactions. All PDE11A isoforms form oligomers (Weeks et al. 2007), as does every PDE (Heikaus et al. 2009; Francis et al. 2011). The GAF-B domain is required for PDE11A dimerization; however, amino acids within the catalytic domain may also facilitate this protein-protein interaction (Weeks et al. 2007). Full-length PDE11A1-4 isoforms all form homo-oligomers (PDE11A1: homotetramers; PDE11A2, 3, and 4: homodimers); whereas, the isolated PDE11A catalytic domain primarily exists as a monomer (although it can form low-affinity dimers) (Weeks et al. 2007). It does not appear that quaternary structure greatly impacts substrate affinity since substrate affinities for cAMP and cGMP are nearly identical for the dimeric PDE11A2 versus the tetrameric PDE11A1 for cAMP and cGMP (Weeks et al. 2007). That said, the effect of oligomerization on catalytic activity has not been directly examined. It is clear, however, that disrupting homodimerization of PDE11A4 dramatically changes both the stability of the protein as well as its subcellular compartmentalization (Pathak et al. 2016). Disrupting homodimerization increases proteolytic degradation of PDE11A4 (Pathak et al. 2016). Further, disrupting homodimerzation shifts PDE11A4 from the membrane to the cytosol of COS-1 cells; whereas, strengthening homodimerization with an A499T mutation shifts PDE11A4 from the cytosol to the membrane (Pathak et al. 2016). Together, these studies are consistent with those examining the PDE2, PDE4, and PDE5 families, which suggest that catalytic function does not require dimerization but that dimerization may indirectly modify activity and subcellular localization by influencing vulnerability to posttranslational modifications (Keravis and Lugnier 2010; Francis et al. 2011).

The C-terminal catalytic domain of PDE11A hydrolyzes both cAMP and cGMP. PDE11A is a dual-specificity PDE, meaning it hydrolyzes both cAMP and cGMP under physiological conditions (cf. Makhlouf et al. 2006). As extensively reviewed elsewhere (Kelly 2015), all PDE11A isoforms hydrolyze cAMP and cGMP comparably well, despite differences in their individual catalytic properties. The PDE11A catalytic domain is most related to that of PDE5A (Yuasa et al. 2001a). As a result, several PDE5A inhibitors bind to and inhibit PDE11A (Weeks et al. 2009). Studies designed to understand the key molecular interactions responsible for the binding of PDE5A inhibitors to PDE11A suggest that a hydrogen bond involving Q869 is a key regulator of PDE11A4 substrate binding (Weeks et al. 2009) (see Fig. 1). Much work remains to understand the intramolecular mechanism regulating PDE11A catalytic activity and substrate/inhibitor affinity.

A Role for PDE11A in Brain Function

PDE11A4 is primarily expressed in the hippocampal formation. PDE11 is the only PDE family whose mRNA expression in the rodent brain is restricted to the hippocampal formation (Kelly et al. 2014) (Fig. 2a). PDE11A4 protein is not only expressed in the rodent hippocampus but also the human hippocampus (Kelly et al. 2010). Outside of the brain, PDE11A4 is also expressed at very low levels within the dorsal root ganglion and at moderate levels in the spinal cord (Fig. 3a). Within the hippocampal formation, PDE11A4 mRNA is expressed in CA1, subiculum, and the amygdalohippocampal area (AHi) (Fig. 2a). PDE11A4 protein expression is also found within these areas, with a three- to tenfold higher expression in the ventral hippocampal formation (VHIPP) versus the dorsal HIPP (DHIPP) (Kelly et al. 2010; Pathak et al. 2016) (Fig. 2b). The extent of enrichment in VHIPP versus DHIPP is dependent on genetic background (Pathak et al. 2016). PDE11A4 protein is expressed in neurons, as opposed to glial cells (Hegde et al. 2016a). Within CA1, PDE11A4 protein is located in a subset of neuronal cell bodies, dendrites and axons (Fig. 2b); whereas, in the subiculum and AHi PDE11A4 protein is restricted to neuronal cell bodies and axon bundles (Hegde et al. 2016a). This suggests that PDE11A4 is compartmentalized in a brain region-specific manner.
PDE11A, Fig. 2

PDE11A4 is the only isoform expressed in brain, with enrichment observed in the ventral hippocampal formation of rodents (known as anterior hippocampus in primates). (a) Left Panel: thionin staining of mouse sagittal sections show brain regions present at ~2.76 mm lateral from Bregma (top) and ~3.00 mm lateral from Bregma (bottom). Right Panel: Autoradiographic in situ hybridization images taken from these sections after labeling with an antisense probe specific for PDE11A4 as per (Kelly et al. 2010, 2014; Kelly 2015). As previously described, PDE11A4 mRNA is almost exclusively expressed in CA1, subiculum (sub), and the amygdalahippocampal area (AHi), with a three- to tenfold enrichment in ventral (v) versus dorsal (d) hippocampus (Kelly et al. 2010, 2014; Kelly 2015). (b) Immunofluorescence using the Fabgennix PD11A-112 antibody on sagittal mouse sections taken from PDE11A wild-type (WT) and knockout (KO) mice ~3.00 mm lateral from Bregma as per Hegde et al. (2016a). Notice robust labeling in the WT tissue compared to the KO tissue, demonstrating specificity of the antibody. As previously reported (Hegde et al. 2016a), PDE11A4 protein is expressed exclusively in neurons, with expression throughout stratum pyramidale (SP; neuronal cell body layer), stratum radiatum (SR; dendritic layer), and stratum oriens (SO; axonal layer) of area CA1, the subiculum, as well as the fimbria (indicated by white arrows; expression in fimbria also confirmed by Western blot – data not shown). Brightness and contrast adjusted to improve graphical clarity of images in 2a. Histogram stretch and gamma adjusted to improve graphical clarity of images in 2b

PDE11A, Fig. 3

PDE11A4 is expressed in the hippocampus, dorsal root ganglion, and spinal cord and is enriched in cytosolic fractions. (a) In addition to the hippocampus (Hipp), reliable PDE11A4 protein expression (i.e., signal in WT but not KO) can also be detected in the dorsal root ganglion (very low levels; DRG) and spinal cord (moderate levels; SC) by Western blot. (b) Biochemical fractionation shows PDE11A4 protein is expressed at different levels throughout the nuclear (Nuc), cytosolic (Cyto, C), soluble membrane (sMemb, sM), and insoluble membrane (iMem) compartments – although note some signal in the iMem compartment is nonspecific as it remains in the KO tissue. Although PDE11A4 protein expression is lowest in the sMem compartment, PDE11A4 expression in this compartment changes in response to genetic (Pathak et al. 2016) and environmental manipulations (Hegde et al. 2016b) with functional consequence, suggesting it is biologically relevant. (c) The subcellular distribution of PDE11A4 protein is unique relative to PDE2A and PDE10A, the closest related PDEs with measurable expression in the hippocampus. PDE11A4 is enriched in the Cyto relative to the sMem compartment; whereas, PDE2A is enriched in the sMem relative to the cyto and PDE10A is found exclusively in the sMem compartment in hippocampus. Note: cerebellum (Cb) included as a negative control on PDE2A blot and striatum (Str) as a positive control for the PDE10A blot. Brightness and contrast adjusted to improve graphical clarity of images

The VHIPP is known to send axonal projections to numerous brain regions, including nucleus accumbens and prefrontal cortex. Tract tracing shows that PDE11A4 expressing neurons project to the nucleus accumbens and at least one other brain region, but not the amygdala (Cembrowski et al. 2016). The fact that PDE11A4 is expressed in the fimbria (Fig. 2b), a major axonal bundle leaving the VHIPP, explains why low levels of PDE11A4 protein can be detected in nucleus accumbens and prefrontal cortex in the absence of appreciable mRNA expression in those regions (Kelly 2015).

In addition to a unique regional expression pattern, PDE11A4 also exhibits a unique age-dependent expression pattern. In rodents, PDE11A4 protein expression is very low on postnatal day 7 but significantly increases with each passing week until postnatal day 28, at which time it stabilizes to young adult levels (Hegde et al. 2016a). Interestingly, following this period of stable expression levels, PDE11A4 levels again increase between young and late adulthood (Kelly et al. 2014). This suggests that PDE11A4 function in the brain may evolve across the lifespan.

The subcellular compartmentalization of PDE11A4 is dynamically regulated. Hippocampal PDE11A4 is found at varying levels in nuclear, cytosolic (Cyto), soluble membrane (sMem), and insoluble membrane (iMem) compartments (Fig. 3b). In the hippocampus, PDE11A4 is most highly expressed in the cytosolic compartment, which stands in contrast to closely related PDE2A and PDE10A that are more highly expressed in the soluble membrane fraction relative to the cytosol (Fig. 3c). Behavioral, genetic, and posttranslational modifications have been identified that modify this subcellular compartmentalization of PDE11A4. For example, social isolation decreases PDE11A4 protein expression specifically within the sMem compartment of the VHIPP, an effect that is sufficient to impair subsequent social behaviors (both social memory formation and social approach behavior) (Hegde et al. 2016b). Similarly, C57BL/6J mice express significantly less PDE11A4 protein than BALB/cJ mice in the sMem compartment of VHIPP (Pathak et al. 2016). The mechanism by which social isolation elicits such compartment-specific effects on PDE11A4 protein expression is not yet known; however, it appears that the compartment-specific effect in the C57BL/6J versus BALB/cJ mice is driven by an amino acid difference at position 499 (a non-phosphorylatable alanine vs. a phosphorylatable threonine, respectively) that directly affects homodimerization at the GAF-B domain (Pathak et al. 2016). As noted above, disrupting homodimerization shifts PDE11A4 from the sMem to the Cyto (Pathak et al. 2016). Given how sensitive PDE11A4 in the sMem is to various manipulations, it is interesting to note that RNA sequencing of VHIPP tissue from PDE11A KO versus WT mice reveals gene expression changes enriched in a number of membrane-related pathways (Hegde et al. 2016b). The ability to restore PDE11A4 to a specific subcellular compartment may become highly relevant as compartment-specific changes in cyclic nucleotide signaling have been associated with Alzheimer’s disease, bipolar disorder, and lithium responsiveness (Casebolt and Jope 1991; Jensen and Mork 1997; Rahman et al. 1997; Mori et al. 1998; Bonkale et al. 1999; Fields et al. 1999; Chang et al. 2003).

PDE11A4 regulates social behaviors and mood stabilization. As described above, PDE11A4 expression is highly enriched in VHIPP versus DHIPP (Kelly et al. 2010, 2014; Kelly 2014, 2015; Hegde et al. 2016a) (Fig. 2), contributing to the biochemical, functional, and anatomical segregation of VHIPP versus DHIPP circuitry (e.g., Roman and Soumireu-Mourat 1988; Papatheodoropoulos and Kostopoulos 2000; Bast and Feldon 2003; Gusev et al. 2005; Fanselow and Dong 2010). As reviewed elsewhere (Kelly 2015), the VHIPP modulates social behaviors (including social learning and memory), mood/affective behaviors (including regulation of emotions as well as fear learning and memory), behavioral flexibility, motivation, sensorimotor gating, and stress responses; whereas, the DHIPP regulates spatial learning and memory, spatial navigation, and contextual representations (c.f., Moser and Moser 1998; Bast and Feldon 2003; Tseng et al. 2008; Fanselow and Dong 2010; Behrendt 2011; also see Roman and Soumireu-Mourat 1988; Marquis et al. 2008; Gruber et al. 2010). As one might expect based on its high expression in the VHIPP, recent studies suggest PDE11A4 is required for intact social behaviors and mood stabilization.

Human studies point to a role for PDE11A4 in mood disorders. Genetic and functional studies in humans suggest PDE11A dysfunction may contribute to the pathophysiology of mood disorders (Kelly 2015). Several studies genetically associate PDE11A with major depressive disorder (MDD) (Wong et al. 2006; Cabanero et al. 2009; Luo et al. 2009), and an additional study associates a PDE11A inactivating mutation with suicide risk in a Utah pedigree (Coon et al. 2013) (Table 2). Interestingly, an additional gene that is genetically associated with suicide risk in the aforementioned study is Plexin B1 (Coon et al. 2013), and Plexin B1 is upregulated in the VHIPP of PDE11A KO mice relative to WT littermates (Hegde et al. 2016b). Pharmacogenomic studies have also examined PDE11A with regard to antidepressant and mood stabilizer responsiveness. In patients with MDD, PDE11A is nominally associated with response to fluoxetine and desipramine (Wong et al. 2006; Luo et al. 2009) but not with response to citalopram or duloxetine (Cabanero et al. 2009; Perlis et al. 2010). In patients with bipolar disorder, PDE11A is genetically associated with lithium responsiveness (Couzin 2008; Kelsoe 2010). Further, in hippocampal neurons derived from induced pluripotent stem cells (IPSC) that were obtained from lithium-responsive patients, lithium decreases PDE11A mRNA (Mertens et al. 2015). This effect is not observed in IPSC-derived hippocampal neurons from lithium-unresponsive patients (Mertens et al. 2015). A potential role for PDE11A in lithium responsivity would be consistent with the fact that many changes in the cAMP cascade have been identified in patients with bipolar disorder (Schreiber and Avissar 1991; Schreiber et al. 1991; Avissar et al. 1997; Rahman et al. 1997; Dowlatshahi et al. 1999; Fields et al. 1999; Chang et al. 2003; Avissar and Schreiber 2006; Fatemi et al. 2008, 2010; Alda et al. 2013), including subcellular compartment-specific changes in cyclic nucleotide signaling (Rahman et al. 1997; Fields et al. 1999; Chang et al. 2003) and cyclic nucleotide signaling changes in response to lithium (Sun et al. 2004; Alda et al. 2013). Given that PDE11A has been genetically associated with suicide risk (Coon et al. 2013) as well as genetically and functionally associated with lithium responsivity (Couzin 2008; Kelsoe 2010; Mertens et al. 2015), it is interesting to note that lithium uniquely decreases the risk of suicide in patients with bipolar disorder (Malhi et al. 2013). As discussed below, preclinical studies suggest PDE11A4 dysfunction may contribute to social deficits that are associated with mood disorders and that PDE11A4 may be a key molecular mechanism controlling lithium responsivity.
PDE11A, Table 2

Genetic studies have linked PDE11A to endocrine dysfunction, tumorigenesis, brain function, and inflammation

PDE11A mutation

Associated disease/pharmacology

Effect of mutation

Refs

Nonsense/missense

   

 fs41X

AD/CC/PA/PC/TT cases and controls

Decreased PDE11A protein

[1–5]

 fs15X

AD cases and controls

Predicted truncation

[1, 2]

 R52T

TT case

Diminished ability to hydrolyze cAMP in HEK293 and MLTC-1 cells

[6–8]

 R184Q

TT/MRKH cases and controls

Not predicted to cause loss of function by SIFT and Polyphen2 prediction algorithms

[7, 9]

 R202C

PC case

Diminished PDE11A function in HEK293 and PC3M cells

[5]

 F205L

AD case

 

[10]

 L218F

CC case

 

[4]

 F258Y

TT case

Diminished ability to hydrolyze cAMP in HEK293 and MLTC-1 cells

[6]

 S275X

CC case

 

[4]

 Q279E

TT cases and controls

 

[7]

 G291R

TT case

Diminished ability to hydrolyze cAMP in HEK293 and MLTC-1 cells

[6]

 N298

TT cases and controls

 

[7]

 R307X

AD/CC cases and controls; carriers versus noncarriers show higher SBP, DBP, waste circumference, BMI, and stroke incidence

Decreased PDE11A mRNA and protein

[1, 2, 4, 7, 10, 11]

 A349T

AT/CC/PC/TT cases and controls

Diminished ability to hydrolyze cAMP in HEK293 and MLTC-1 cells

[4–8, 10]

 E382X

CC case

Predicted truncation

[4]

 A499T

BALB/cJ mice

Promotes homodimerization and shifts PDE11A from the cytosol to the membrane

[12]

 R545X

TT case

Loss of PDE11A4 protein expression, emergence of 60 kDA species; loss of catalytic activity in HEK293T cells

[7]

 I552T

TT cases and controls

 

[7]

 K568R

TT case

Decreased PDE11A4 protein expression; reduced catalytic activity in HEK293T cells

[7]

 S570P

TT cases and controls

 

[7]

 D609N

AD/TT cases and controls

Diminished ability to decrease global cAMP signaling in H295R, MLTC-1, and HEK293 cells

[5, 7, 10]

 Y644C

TT cases and controls

 

[7]

 Y658C

AD/PC case

Loss of PDE11A function in HEK293 and PC3M cells

[5, 8]

 H664G

AD case

 

[10]

 Y727C

AD/CC/PA/TT cases and controls; PC cases > controls

Diminished ability to hydrolyze cAMP in MLTC-1 cells

[3–8, 10]

 L756Q

MRKH case (no controls assessed)

Predicted to cause loss of function by SIFT and Polyphen2 prediction algorithms

[9]

 R804H

AD/CC/PA/PC/TT cases and controls

Diminished or lost ability to hydrolyze cAMP in HEK293, HeLA, and MLTC-1 cells; loss of ability to hydrolyze cGMP in HeLA but not HEK293 cells

[1–8, 10]

 V820M

TT cases

Diminished ability to hydrolyze cAMP in HEK293 and MLTC-1 cells

[6, 7]

 E840K

PC cases

Loss of PDE11A function in PC3M cells, decreased PDE11A function in HEK293 cells

[5]

 R867G

AD/CC/PA/PC/TT cases and controls

Diminished ability to hydrolyze cAMP in MLTC-1 cells and complete loss of ability to hydrolyze cGMP in HEK293 cells

[1–8, 10]

 I873T

CC case

 

[4]

 M878V (a.k.a. rs74357545)

AD/CC/PA/PC/TT cases and controls; Utah pedigree suicides > non-pedigree suicides and non-suicide controls

Diminished ability to decrease global cAMP signaling in H295R, MLTC-1, and HEK293 cells

[3–8, 10, 13]

 Higher overall incidence of missense/nonsense mutations in cases versus controls

AD, PC, and TT but not PA

 

[2–6, 8, 10] but see [7]

Exonic insertion

   

 rs3830637/2758_2760ins TCC/S920ins in exon 23

AD/PA/TT/MRKH cases and controls

 

[3, 6, 9, 10]

Synonymous

   

 L49L

AD case and controls

 

[6, 10]

 Q118Q

AD cases

 

[10]

 L160L

AD case

 

[10]

 C230C

AD cases and controls

 

[6, 10]

 E421E

AD/PA/TT cases and controls; ACC < controls; sporadic TT < controls

 

[3, 6, 7, 10]

Intronic

   

 rs2037757/c.1367 + 4521C > T

MDD

 

[14]

 rs4893975/c.2646 + 7848 T > C

MDD

 

[15]

 rs3770018/c.2424-558 T > G

MDD

 

[14, 16]

 rs3770018/c.2424-558 T > G

MDD remission with fluoxetine; not duloxetine

 

[16, 17]

 rs1880916/c.1072-25516C > T

MDD remission with fluoxetine/desipramine; not citalopram; not duloxetine

 

[15–17]

 rs7585543/c.1788 + 13290A > G

Li + responsivity in bipolar disorder

 

[18]

 rs959157/C.912 + 601A > G

Cushing syndrome

 

[1]

 rs11684634/c.1789-12870G > T

Allergic asthma in PRAM and B58C adult cohort (not child cohort)

 

[19]

 rs11687573/c.162 + 16198A > G

Asthma in FHS

 

[19]

 rs1405716/c.2647-6509C > T

Asthma in childhood, asthma MP

 

[19]

 rs1997209/c.2646 + 16239A > G

Asthma in childhood, asthma MP

 

[19]

 rs4893980/ c.2345 + 7028A > G

Extrapulmonary tuberculosis

 

[20]

 rs13012088/c.1072-3c/t

AD/PA/TT cases and controls

 

[3, 6, 7, 10]

 c.1501-107A > G

PA cases and controls

 

[3]

 c.1576 + 67A > CCT

PA cases and controls

 

[3]

 c.1577-3c/t

TT case and control

 

[6]

 c.1644 + 26insGTTTATA

AD/TTcases and controls; ACC C/C > controls

 

[6, 10]

 c.1737 + 56A > T

TT cases and controls; sporadic TT > controls

 

[7]

 c.1738-34G > T

TT cases and controls

 

[7]

 c.2424-46C/T

PA cases and controls

 

[3]

 c.2563-26G > A

TT cases and controls; familial TT > controls

 

[7]

ACC adrenocortical cancer, AD adrenal dysfunction (including adrenal tumors, hyperplasias, Cushing syndrome), B58C British 1958 Birth Cohort, BMI body mass index, CC Carney complex (can include primary pigmented nodular adrenocortical disease with/without testicular tumors), DBP diastolic blood pressure, FHS Framingham Heart Study, MDD major depressive disorder, MP management program, MRKH Mayer–Rokitansky–Kuster–Hauser syndrome, PA pituitary adenoma, PC prostate cancer, PRAM perinatal risk of asthma in infants with asthmatic mothers, SBP systolic blood pressure, TT testicular tumors

1. Horvath A, et al. A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia. Nat Genet. 2006;38(7):794–800.

2. Horvath A, et al. Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population. Cancer Res. 2006;66(24):11571–5.

3. Peverelli E, et al. Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients. Eur J Endocrinol. 2009;161(5):687–94.

4. Libe R, et al. Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype. J Clin Endocrinol Metab. 2011;96(1):E208–14.

5. Faucz FR, et al. Phosphodiesterase 11A (PDE11A) genetic variants may increase susceptibility to prostatic cancer. J Clin Endocrinol Metab. 2011;96(1):E135–40.

6. Horvath A, et al. Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors. Cancer Res. 2009;69(13):5301–6.

7. Pathak A, et al. Rare inactivating PDE11A variants associated with testicular germ cell tumors. Endocr Relat Cancer. 2015;22(6):909–17.

8. Vezzosi D, et al. Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): functional variants may contribute to genetic susceptibility of bilateral adrenal tumors. J Clin Endocrinol Metab. 2012;97(11):E2063–9.

9. Chen MJ, et al. Concurrent exome-targeted next-generation sequencing and single nucleotide polymorphism array to identify the causative genetic aberrations of isolated Mayer-Rokitansky-Kuster-Hauser syndrome. Hum Reprod. 2015;30(7):1732–42.

10. Libe R, et al. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. Clin Cancer Res. 2008;14(12):4016–24.

11. Ohlsson T, et al. A stop-codon of the phosphodiesterase 11A gene is associated with elevated blood pressure and measures of obesity. J Hypertens. 2016;34(3):445–51; discussion 451.

12. Pathak G, et al. PDE11A negatively regulates lithium responsivity. Mol Psychiatry. 2016.

13. Coon H, et al. Genetic risk factors in two Utah pedigrees at high risk for suicide. Transl Psychiatry. 2013;3:e325.

14. Luo HR, et al. Association of PDE11A global haplotype with major depression and antidepressant drug response. Neuropsychiatr Dis Treat. 2009;5:163–70.

15. Cabanero M, et al. Association study of phosphodiesterase genes in the sequenced treatment alternatives to relieve depression sample. Pharmacogenet Genomics. 2009;19(3):235–8.

16. Wong ML, et al. Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. Proc Natl Acad Sci U S A. 2006;103(41):15124–9.

17. Perlis RH, et al. Failure to replicate genetic associations with antidepressant treatment response in duloxetine-treated patients. Biol Psychiatry. 2010;67(11):1110–3.

18. Kelsoe J. Method to predict response to treatment for psychiatric illnesses. In U.P.T. Office. Oakland: The Regents of the University of California; 2010. p. 1.

19. DeWan AT, et al. PDE11A associations with asthma: results of a genome-wide association scan. J Allergy Clin Immunol. 2010;126(4):871–3 e9.

20. Oki NO, et al. Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study. BMC Res Notes. 2011;4:28.

Rodent studies show PDE11A4 is required for intact social interactions. Consistent with the fact that PDE11A4 expression throughout the body is so restricted, PDE11A KO mice exhibit a limited number of phenotypes. For example, single-housed PDE11A KO mice show normal long-term memory for contextual and cued fear conditioning 24 h after training (Kelly et al. 2010). In addition, both single-housed and group-housed PDE11A KO mice exhibit normal baseline anxiety- and depression-related behaviors (Kelly et al. 2010; Kelly in press). That said, group-housed – but not single-housed – PDE11A KO mice show greater antidepressant effects of lithium than do WT littermates ((Pathak et al. 2016); discussed at further length below). Although single-housed PDE11A KO mice exhibit normal prepulse inhibition (PPI) of acoustic startle relative to WT mice (Kelly et al. 2010), group-housed PDE11A KO mice show a limited decrease in PPI (limited to the lowest prepulse intensity) (Kelly in press). In contrast, group-housed PDE11A KO mice demonstrate normal locomotor activity in an open field (Kelly in press), but single-housed PDE11A KO mice demonstrate hyperactivity in an open field (Kelly et al. 2010). Together, these data suggest that housing condition can alter the behavioral consequence of PDE11A deletion, which is consistent with the fact that social isolation decreases PDE11A4 protein expression in the sMem compartment of VHIPP (discussed above) (Hegde et al. 2016b).

Not only does social experience affect PDE11A4 expression, but PDE11A is required for normal social behaviors. PDE11A heterozygous (HT) and KO mice show sex-specific and context-dependent deficits in social approach behavior (Kelly et al. 2010; Hegde et al. 2016b). Whether or not both male and female PDE11A mutant mice show deficits in social approach, and the magnitude of the social approach deficit across the sexes, depends on the strain of the stimulus mouse used in the assay and whether the alternative choice to the novel mouse is a novel object or a familiar cagemate (Hegde et al. 2016b). It is clear that other mice sense the aberrant social behaviors exhibited by PDE11A KO mice, because C57BL/6J mice – considered a social mouse strain – prefer to spend time interacting with a PDE11A WT mouse versus its KO littermate (Hegde et al. 2016b). In contrast, PDE11A KO mice prefer to spend time interacting with a novel PDE11A KO mice versus a novel PDE11A WT mouse (Hegde et al. 2016b). Consistent with the fact that PDE11A is required for normal social interactions, RNA sequencing of PDE11A KO versus WT littermates shows VHIPP gene expression changes enriched in the oxytocin signaling pathway (Hegde et al. 2016b), a signaling cascade critical to the neurobiology of social behaviors (c.f. Viero et al. 2010; Ebstein et al. 2012; Lukas and Neumann 2013; Stoesz et al. 2013).

Rodent studies show PDE11A4 is required for social memory formation. Although PDE11A KO mice demonstrate normal short-term memory (STM) for social odor recognition (SOR) and social transmission of food preference (STFP), they fail to show any long-term memory (LTM) 24 h after training (Kelly et al. 2010; Hegde et al. 2016a). The ability of PDE11A KO mice to retrieve a STM but not a LTM suggests that PDE11A is not required for learning nor memory retrieval per se, but rather PDE11A is required to consolidate a STM into a long-lasting form (Hegde et al. 2016a). In contrast, PDE11A KO mice are able to retrieve a LTM for contextual/cued fear conditioning (Kelly et al. 2010) and nonsocial odor recognition memory 24 h after training (Hegde et al. 2016a), suggesting the SOR and STFP LTM deficits are due to the social nature of these memories. The fact that PDE11A4 is required for social memory formation but not nonsocial memory formation is consistent with the fact that PDE11A4 is enriched in the VHIPP (Kelly et al. 2010, 2014; Kelly 2014, 2015; Hegde et al. 2016a) and the fact that PDE11A regulates gene expression in the oxytocin signaling pathway (Hegde et al. 2016b). Indeed, deletion of oxytocin similarly impairs the ability of mice to form social memories without affecting their ability to form nonsocial memories (Ferguson et al. 2000). Changes in glutamatergic signaling may also contribute to the memory consolidation deficits observed in PDE11A KO mice. PDE11A KO mice exhibit biochemical changes affecting AMPA receptor signaling in the hippocampus, including reduced phosphorylation of the GluR1 receptor subunit and reduced expression of transmembrane AMPA receptor-associated proteins, and are more sensitive to the hyperlocomotor effects MK-801, an NMDA receptor antagonist (Kelly et al. 2010). This sensitivity to psychostimulants appears to be at least somewhat specific for the glutamatergic system as PDE11A KO mice responded normally to the hyperactivating effects of a dopaminergic psychostimulant (Kelly et al. 2010). An impairment in protein synthesis, which is required to transition a STM to a LTM, may also contribute to the memory deficits observed in PDE11A KO mice. In VHIPP, PDE11A KO mice show reduced phosphorylation of the ribosomal protein S6 at serines 235/236 relative that is likely due to decreased expression of ribosomal S6 kinase 2 (RSK2) (Hegde et al. 2016a). Determining which, if any, of these mechanisms underlies the social memory deficits observed in PDE11A KO mice will be of interest to future studies.

Interestingly, PDE11A mutant mice show deficits in social memory formation at an earlier age than they show deficits in social approach behaviors. Although adolescent PDE11A KO mice already have deficits in SOR and STFP LTM formation (Hegde et al. 2016a), they exhibit normal social approach behaviors relative to WT littermates (Hegde et al. 2016b). As discussed elsewhere (Hegde et al. 2016b; Kelly in press), this may suggest that social approach deficits observed in adult PDE11A mutant mice may come as a result of not being able to form memories for what is and what is not a socially acceptable behavior. Certainly in humans with intellectual disabilities, a lack of appropriate social skills during childhood predicts poorer quality friendships during adolescence (Tipton et al. 2013).

Rodent studies suggest PDE11A4 negatively regulates lithium responsivity. As noted above, lithium responsivity in patients with bipolar disorder has been genetically and functionally associated with PDE11A (Couzin 2008; Kelsoe 2010; Mertens et al. 2015), and studies in mice suggest lithium responsivity is negatively regulated by PDE11A4 (Pathak et al. 2016). PDE11A4 mRNA and protein expression are relatively low in VHIPP and DHIPP of C57BL/6J mice and 129S6/SvEvTac mice, both of which are strains that respond well to lithium (Pathak et al. 2016). In comparison, PDE11A mRNA and protein expression are relatively high in the VHIPP and DHIPP of BALB/cJ mice, which fail to respond to lithium (Pathak et al. 2016). Consistent with this correlation across strains, decreasing PDE11A4 is sufficient to increase lithium responsivity, as demonstrated in studies using PDE11A mutant mice (Pathak et al. 2016). Why reduced PDE11A expression correlates with improved lithium responsivity remains to be determined.

Data collected in mouse models suggests that reduced PDE11A4 expression represents a specific pathophysiology lithium happens to treat well, as opposed to the idea that reducing PDE11A4 expression may augment lithium’s beneficial effects (Pathak et al. 2016). As described above, PDE11A mutant mice exhibit a number of behavioral phenotypes relevant to psychiatric disease (Kelly et al. 2010; Hegde et al. 2016a, b). Further, both IPSC-derived hippocampal neurons from bipolar patients and VHIPP of PDE11A KO mice show gene expression changes that are enriched in the neuroactive-ligand receptor pathway as well as increased neural activity (Kelly et al. 2010; Hegde et al. 2016b; Mertens et al. 2015). PDE11A KO mice also show increased hippocampal expression of the proinflammatory cytokine IL-6 (Pathak et al. 2016), which may be considered a mood-disorder biomarker since a number of studies have identified elevated IL-6 signaling in patients with depression, mania, and suicidal ideation (Maes et al. 1995, 1997; Simon et al. 2008; Brietzke et al. 2009; Dowlati et al. 2010; Khandaker et al. 2014; Niculescu et al. 2015) that is reversed by lithium (Watanabe et al. 2014). That said, the fact that lithium decreases PDE11A4 expression in IPSC-derived hippocampal neurons from lithium-responsive but not unresponsive patients with bipolar disorder more readily argues that decreasing PDE11A expression is a mechanism by which lithium elicits its beneficial effects (Mertens et al. 2015). It will be of utmost importance to uncover why lower levels of PDE11A lead to improved lithium response in order to understand if a PDE11A inhibitor might represent a possible adjuvant treatment capable of improving lithium responsivity.

PDE11A Loss-of-Function Mutations Are Associated with Increased Tumor Risk

As thoroughly reviewed elsewhere (Kelly 2015), a large number of nonsense (i.e., truncating mutation), missense (i.e., nonsynonymous coding), synonymous, and intronic mutations have been identified in the PDE11A gene (Table 2). A thorough review of the literature to date identifies numerous common mutations found in both patients and control subjects (Table 2). In addition, a number of rare mutations have also been reported in a small number of patients with various tumor types but not controls (Table 2). PDE11A mutations characterized to date largely produce a loss-of-function phenotype either by directly reducing expression, decreasing catalytic activity, or displacing the enzyme from its cognate pool of cyclic nucleotides; however, it is important to note that the effects of the mutations are often cell-type specific (Table 2; see (Kelly 2015) for detailed review of functional effects). With regard to the mutations that have been found in both patients and controls, any single mutation is rarely reported to occur more frequently in patients. That said, a number of studies have shown that patients with adrenal dysfunction (including adrenal tumors, hyperplasias, Cushing syndrome), prostate cancer, and testicular tumors – but not pituitary adenomas – exhibit a generally higher incidence of PDE11A missense/nonsense mutations relative to control subjects (Horvath et al. 2006, 2009; Libe et al. 2008, 2011; Peverelli et al. 2009; Faucz et al. 2011; Vezzosi et al. 2012, but see Pathak et al. 2015). Together, these data suggest that the loss of PDE11A function is not likely sufficient to cause endocrine tumors but may increase disease risk (Kelly 2015). Indeed, PDE11A KO mice do not show any increased incidence of tumors up to 1 year of age (Kelly et al. 2010).

In addition to the direct effect of these loss-of-function mutations, there appear to be indirect mechanisms capable of compromising PDE11A function in tumors. For example, reduced PDE11A protein expression has been reported in adrenal tumors in absence of any PDE11A missense mutations (Boikos et al. 2008). Increased CpG methylation, which generally correlates with decreased transcription, may be one such indirect mechanism downregulating PDE11A expression as increased CpG methylation of the PDE11A promoter was identified in leukocytes from patients with testicular tumors relative to healthy controls (Mirabello et al. 2012). Another possible indirect mechanism that may reduce PDE11A expression is an overactivation of the nuclear protein NONO and/or the exoribonuclease XNR2. Normally, NONO stimulates XNR2 to break down PDE11A mRNA, which leads to an increase in adrenocorticotropin hormone-stimulated cAMP levels and increased glucocorticoid synthesis (Lu and Sewer 2015). If PDE11A-targeted therapeutics are to be developed to reduce tumor risk, it will be essential for future studies to understand how a given PDE11A mutation or indirect mechanism actually decreases PDE11A function.

Possible Role for PDE11A in Inflammation

Emerging studies suggest PDE11A may play a role in regulating inflammation and, possibly, immune function (Kelly 2015). PDE11A is genetically linked to asthma in several genome-wide association cohorts that previously demonstrated an association between asthma and PDE4D (DeWan et al. 2010; Table 2). A separate study conducted in patients infected with M. tuberculosis genetically associates PDE11A with the risk of developing extrapulmonary tuberculosis versus remaining asymptomatic (Oki et al. 2011). Rodent studies demonstrate a functional role for PDE11A in cell types relevant to inflammation and immune function. Although PDE11A mRNA expression appears to be negligible in resident macrophages and “resting” peritoneal exudate macrophages (PEMs) from rat, it is robustly upregulated in PEMs following a 24-h incubation with the bacterial endotoxin lipopolysaccharide (LPS) (Witwicka et al. 2007), suggesting PDE11A may play a role in activating macrophages. In addition, mouse regulatory T cells express significantly lower levels of PDE11A mRNA and catalytic activity than do activated conventional T cells (Bazhin et al. 2010), suggesting PDE11A may modulate regulatory T-cell suppression of antigen-activated conventional T cells. Finally, reducing PDE11A expression in brain appears to increase expression of the proinflammatory cytokine IL-6 in dorsal hippocampus of mice (Pathak et al. 2016). In summary, studies to date suggest PDE11A may be a key regulator of inflammatory processes; however, whether PDE11A regulates inflammation primarily by regulating cytokine release, modulating susceptibility to bacterial invasion, or some other mechanism remains to be determined.

Summary

PDE11 is the most recently discovered 3′,5′-cyclic nucleotide PDE family. The PDE11A gene encodes four isoforms (PDE11A1-4), each of which breaks down both cAMP and cGMP. PDE11A1-4 each has a unique N-terminal regulatory region, suggesting the ability to uniquely control each isoform. Indeed, intramolecular signals within the N-terminal region, such as phosphorylation, cGMP/cGMP-analogue binding of the GAF-A domain, and homodimerization at the GAF-B domain, have been shown to alter the subcellular compartmentalization and catalytic function of PDE11A4 in particular. A thorough review of tissue expression studies suggests that PDE11A is reliably expressed in only a few tissues across the body, most notably the central nervous system (hippocampus, spinal cord, and DRGs). Consistent with the conclusion that PDE11A is expressed in few peripheral organs, PDE11A knockout mice remain physically healthy well into late age (Kelly et al. 2010). To date, PDE11A has been shown to play an important role in regulating brain function and behavior and may play a role in tumorigenesis and inflammation/immune activation. It will be of great interest to future studies to expand our understanding of the upstream regulation of PDE11A and the downstream consequence of its function at the molecular level and how PDE11A expression and function may evolve across the lifespan.

Notes

Acknowledgments

The author thanks Jennifer Klett for technical assistance with Fig. 2a, Baher Ibrahim for technical assistance with Fig. 2b, Neema Patel for technical assistance with Fig. 3b, and William Capell for technical assistance with Fig. 3c. This work was funded by 1R01MH101130 from NIMH and a NARSAD Young Investigator Award from the Brain & Behavior Research Foundation (all awards to MPK).

References

  1. Alda M, Shao L, Wang JF, Lopez de Lara C, Jaitovich-Groisman I, Lebel V, et al. Alterations in phosphorylated cAMP response element-binding protein (pCREB) signaling: an endophenotype of lithium-responsive bipolar disorder? Bipolar Disord. 2013;15:824–31. doi: 10.1111/bdi.12131.PubMedCrossRefPubMedCentralGoogle Scholar
  2. Avissar S, Schreiber G. The involvement of G proteins and regulators of receptor-G protein coupling in the pathophysiology, diagnosis and treatment of mood disorders. [Review] [109 refs]. Clin Chim Acta. 2006;366:37–47.PubMedCrossRefGoogle Scholar
  3. Avissar S, Nechamkin Y, Barki-Harrington L, Roitman G, Schreiber G. Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder are state dependent. J Affect Disord. 1997;43:85–93.PubMedCrossRefGoogle Scholar
  4. Bast T, Feldon J. Hippocampal modulation of sensorimotor processes. Prog Neurobiol. 2003;70:319–45.PubMedCrossRefGoogle Scholar
  5. Bazhin AV, Kahnert S, Kimpfler S, Schadendorf D, Umansky V. Distinct metabolism of cyclic adenosine monophosphate in regulatory and helper CD4+ T cells. Mol Immunol. 2010;47:678–84. doi: 10.1016/j.molimm.2009.10.032.PubMedCrossRefPubMedCentralGoogle Scholar
  6. Behrendt R-P. Neuroanatomy of social behavior: an evolutionary and psychoanalytic perspective. London: Karnac Books; 2011.Google Scholar
  7. Bender AT, Beavo JA. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev. 2006;58:488–520. doi: 10.1124/pr.58.3.5.PubMedCrossRefPubMedCentralGoogle Scholar
  8. Boikos SA, Horvath A, Heyerdahl S, Stein E, Robinson-White A, Bossis I, et al. Phosphodiesterase 11A expression in the adrenal cortex, primary pigmented nodular adrenocortical disease, and other corticotropin-independent lesions. Horm Metab Res. 2008;40:347–53. doi: 10.1055/s-2008-1076694.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bonkale WL, Cowburn RF, Ohm TG, Bogdanovic N, Fastbom J. A quantitative autoradiographic study of [3H]cAMP binding to cytosolic and particulate protein kinase A in post-mortem brain staged for Alzheimer’s disease neurofibrillary changes and amyloid deposits. Brain Res. 1999;818:383–96.PubMedCrossRefGoogle Scholar
  10. Brietzke E, Stertz L, Fernandes BS, Kauer-Sant’anna M, Mascarenhas M, Escosteguy Vargas A, et al. Comparison of cytokine levels in depressed, manic and euthymic patients with bipolar disorder. J Affect Disord. 2009;116:214–7. doi: 10.1016/j.jad.2008.12.001.PubMedCrossRefPubMedCentralGoogle Scholar
  11. Cabanero M, Laje G, Detera-Wadleigh S, McMahon FJ. Association study of phosphodiesterase genes in the sequenced treatment alternatives to relieve depression sample. Pharmacogenet Genomics. 2009;19:235–8. doi: 10.1097/FPC.0b013e328320a3e2.PubMedPubMedCentralCrossRefGoogle Scholar
  12. Capell WR, Fisher JL, Kelly MP. N-terminal phosphorylation alters the subcellular compartmentalization of PDE11A4. in preparation.Google Scholar
  13. Casebolt TL, Jope RS. Effects of chronic lithium treatment on protein kinase C and cyclic AMP-dependent protein phosphorylation. Biol Psychiatry. 1991;29:233–43.PubMedCrossRefGoogle Scholar
  14. Cembrowski MS, Bachman JL, Wang L, Sugino K, Shields BC, Spruston N. Spatial gene-expression gradients underlie prominent heterogeneity of CA1 pyramidal neurons. Neuron. 2016. doi: 10.1016/j.neuron.2015.12.013.
  15. Chang A, Li PP, Warsh JJ. Altered cAMP-dependent protein kinase subunit immunolabeling in post-mortem brain from patients with bipolar affective disorder.[erratum appears in J Neurochem. 2003 Apr;85(1):286.]. J Neurochem. 2003;84:781–91.PubMedCrossRefGoogle Scholar
  16. Coon H, Darlington T, Pimentel R, Smith KR, Huff CD, Hu H, et al. Genetic risk factors in two Utah pedigrees at high risk for suicide. Transl Psychiatry. 2013;3:e325. doi: 10.1038/tp.2013.100.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Couzin J. Science and commerce. Gene tests for psychiatric risk polarize researchers. Science. 2008;319:274–7. doi: 10.1126/science.319.5861.274.PubMedCrossRefPubMedCentralGoogle Scholar
  18. DeWan AT, Triche EW, Xu X, Hsu LI, Zhao C, Belanger K, et al. PDE11A associations with asthma: results of a genome-wide association scan. J Allergy Clin Immunol. 2010;126:871-3 e9. doi: 10.1016/j.jaci.2010.06.051.
  19. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–57. doi: 10.1016/j.biopsych.2009.09.033.PubMedCrossRefPubMedCentralGoogle Scholar
  20. Dowlatshahi D, MacQueen GM, Wang JF, Reiach JS, Young LT. G protein-coupled cyclic AMP signaling in postmortem brain of subjects with mood disorders: effects of diagnosis, suicide, and treatment at the time of death. J Neurochem. 1999;73:1121–6.PubMedCrossRefGoogle Scholar
  21. Ebstein RP, Knafo A, Mankuta D, Chew SH, Lai PS. The contributions of oxytocin and vasopressin pathway genes to human behavior. Horm Behav. 2012;61:359–79. doi: 10.1016/j.yhbeh.2011.12.014.PubMedCrossRefPubMedCentralGoogle Scholar
  22. Edwards HV, Christian F, Baillie GS. cAMP: novel concepts in compartmentalised signalling. Semin Cell Dev Biol. 2012;23:181–90. doi: 10.1016/j.semcdb.2011.09.005.PubMedCrossRefPubMedCentralGoogle Scholar
  23. Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65:7–19. doi: 10.1016/j.neuron.2009.11.031.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Fatemi SH, Reutiman TJ, Folsom TD, Lee S. Phosphodiesterase-4A expression is reduced in cerebella of patients with bipolar disorder. Psychiatr Genet. 2008;18:282–8.PubMedCrossRefGoogle Scholar
  25. Fatemi SH, Folsom TD, Reutiman TJ, Vazquez G. Phosphodiesterase signaling system is disrupted in the cerebella of subjects with schizophrenia, bipolar disorder, and major depression. Schizophr Res. 2010;119:266–7. doi: 10.1016/j.schres.2010.02.1055.PubMedCrossRefPubMedCentralGoogle Scholar
  26. Faucz FR, Horvath A, Rothenbuhler A, Almeida MQ, Libe R, Raffin-Sanson ML, et al. Phosphodiesterase 11A (PDE11A) genetic variants may increase susceptibility to prostatic cancer. J Clin Endocrinol Metab. 2011;96:E135–40. doi: 10.1210/jc.2010-1655.PubMedCrossRefPubMedCentralGoogle Scholar
  27. Fawcett L, Baxendale R, Stacey P, McGrouther C, Harrow I, Soderling S, et al. Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A. Proc Natl Acad Sci U S A. 2000;97:3702–7. doi: 10.1073/pnas.050585197.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Ferguson JN, Young LJ, Hearn EF, Matzuk MM, Insel TR, Winslow JT. Social amnesia in mice lacking the oxytocin gene. Nat Genet. 2000;25:284–8. doi: 10.1038/77040.PubMedCrossRefPubMedCentralGoogle Scholar
  29. Fields A, Li PP, Kish SJ, Warsh JJ. Increased cyclic AMP-dependent protein kinase activity in postmortem brain from patients with bipolar affective disorder. J Neurochem. 1999;73:1704–10.PubMedCrossRefGoogle Scholar
  30. Francis SH, Busch JL, Corbin JD, Sibley D. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev. 2010;62:525–63. doi: 10.1124/pr.110.002907.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev. 2011;91:651–90. doi: 10.1152/physrev.00030.2010.PubMedCrossRefPubMedCentralGoogle Scholar
  32. Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz JE. cAMP is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11. J Biol Chem. 2006;281:2841–6. doi: 10.1074/jbc.M511468200.PubMedCrossRefPubMedCentralGoogle Scholar
  33. Gross-Langenhoff M, Stenzl A, Altenberend F, Schultz A, Schultz JE. The properties of phosphodiesterase 11A4 GAF domains are regulated by modifications in its N-terminal domain. FEBS J. 2008;275:1643–50. doi: 10.1111/j.1742-4658.2008.06319.x.PubMedCrossRefPubMedCentralGoogle Scholar
  34. Gruber AJ, Calhoon GG, Shusterman I, Schoenbaum G, Roesch MR, O’Donnell P. More is less: a disinhibited prefrontal cortex impairs cognitive flexibility. J Neurosci. 2010;30:17102–10. doi: 10.1523/JNEUROSCI.4623-10.2010.PubMedPubMedCentralCrossRefGoogle Scholar
  35. Gusev PA, Cui C, Alkon DL, Gubin AN. Topography of Arc/Arg3.1 mRNA expression in the dorsal and ventral hippocampus induced by recent and remote spatial memory recall: dissociation of CA3 and CA1 activation. J Neurosci. 2005;25:9384–97.PubMedCrossRefGoogle Scholar
  36. Hegde S, Capell WR, Ibrahim BA, Klett J, Patel NS, Sougiannis AT, et al. Phosphodiesterase 11A (PDE11A), enriched in ventral hippocampus neurons, is required for consolidation of social but not nonsocial memories in mice. Neuropsychopharmacology. 2016a;41:2920-31 doi: 10.1038/npp.2016.106.
  37. Hegde S, Ji H, Oliver D, Patel NS, Poupore N, Shtutman M, et al. PDE11A regulates social behaviors and is a key mechanism by which social experience sculpts the brain. Neuroscience. 2016b;335:151–69. doi: 10.1016/j.neuroscience.2016.08.019.PubMedPubMedCentralCrossRefGoogle Scholar
  38. Heikaus CC, Pandit J, Klevit RE. Cyclic nucleotide binding GAF domains from phosphodiesterases: structural and mechanistic insights. Structure. 2009;17:1551–7. doi: 10.1016/j.str.2009.07.019.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Hetman JM, Robas N, Baxendale R, Fidock M, Phillips SC, Soderling SH, et al. Cloning and characterization of two splice variants of human phosphodiesterase 11A. Proc Natl Acad Sci U S A. 2000;97:12891–5. doi: 10.1073/pnas.200355397.PubMedPubMedCentralCrossRefGoogle Scholar
  40. Horvath A, Giatzakis C, Robinson-White A, Boikos S, Levine E, Griffin K, et al. Adrenal hyperplasia and adenomas are associated with inhibition of phosphodiesterase 11A in carriers of PDE11A sequence variants that are frequent in the population. Cancer Res. 2006;66:11571–5. doi: 10.1158/0008-5472.CAN-06-2914.PubMedCrossRefPubMedCentralGoogle Scholar
  41. Horvath A, Korde L, Greene MH, Libe R, Osorio P, Faucz FR, et al. Functional phosphodiesterase 11A mutations may modify the risk of familial and bilateral testicular germ cell tumors. Cancer Res. 2009;69:5301–6. doi: 10.1158/0008-5472.CAN-09-0884.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Jager R, Russwurm C, Schwede F, Genieser HG, Koesling D, Russwurm M. Activation of PDE10 and PDE11 phosphodiesterases. J Biol Chem. 2012;287:1210–9. doi: 10.1074/jbc.M111.263806.PubMedCrossRefPubMedCentralGoogle Scholar
  43. Jensen JB, Mork A. Altered protein phosphorylation in the rat brain following chronic lithium and carbamazepine treatments. Eur Neuropsychopharmacol. 1997;7:173–9.PubMedCrossRefGoogle Scholar
  44. Kelly MP. Putting together the pieces of phosphodiesterase distribution patterns in the brain: a jigsaw puzzle of cyclic nucleotide regulation. In: Brandon NJ, West AR, editors. Cyclic nucleotide phosphodiesterases in the central nervous system: from biology to disease. Hoboken: Wiley; 2014.Google Scholar
  45. Kelly MP. Does phosphodiesterase 11A (PDE11A) hold promise as a future therapeutic target? Curr Pharm Des. 2015;21:389–416.PubMedCrossRefGoogle Scholar
  46. Kelly MP. A role for PDE11A in the formation of social memories and the stabilization of mood. In: Xu J, Zhang H, O’Donnell JM, editors. Phosphodiesterases: CNS functions and diseases. Springer; in press.Google Scholar
  47. Kelly MP, Brandon NJ. Differential function of phosphodiesterase families in the brain: gaining insights through the use of genetically modified animals. Prog Brain Res. 2009;179:67–73. doi: 10.1016/S0079-6123(09)17908-6.PubMedCrossRefPubMedCentralGoogle Scholar
  48. Kelly MP, Logue SF, Brennan J, Day JP, Lakkaraju S, Jiang L, et al. Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes. Proc Natl Acad Sci U S A. 2010;107:8457–62. doi: 10.1073/pnas.1000730107.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Kelly MP, Adamowicz W, Bove S, Hartman AJ, Mariga A, Pathak G, et al. Select 3′,5′-cyclic nucleotide phosphodiesterases exhibit altered expression in the aged rodent brain. Cell Signal. 2014;26:383–97. doi: 10.1016/j.cellsig.2013.10.007.PubMedCrossRefPubMedCentralGoogle Scholar
  50. Kelsoe J. Method to predict response to treatment for psychiatric illnesses. Oakland: The Regents of the University of California; 2010.Google Scholar
  51. Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs. Curr Pharm Des. 2010;16:1114–25.PubMedCrossRefGoogle Scholar
  52. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiat. 2014;71:1121–8. doi: 10.1001/jamapsychiatry.2014.1332.CrossRefGoogle Scholar
  53. Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology. 2010;59(6):367–74.PubMedCrossRefGoogle Scholar
  54. Libe R, Fratticci A, Coste J, Tissier F, Horvath A, Ragazzon B, et al. Phosphodiesterase 11A (PDE11A) and genetic predisposition to adrenocortical tumors. Clin Cancer Res. 2008;14:4016–24. doi: 10.1158/1078-0432.CCR-08-0106.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Libe R, Horvath A, Vezzosi D, Fratticci A, Coste J, Perlemoine K, et al. Frequent phosphodiesterase 11A gene (PDE11A) defects in patients with Carney complex (CNC) caused by PRKAR1A mutations: PDE11A may contribute to adrenal and testicular tumors in CNC as a modifier of the phenotype. J Clin Endocrinol Metab. 2011;96:E208–14. doi: 10.1210/jc.2010-1704.PubMedCrossRefPubMedCentralGoogle Scholar
  56. Lu JY, Sewer MB. p54nrb/NONO regulates cyclic AMP-dependent glucocorticoid production by modulating phosphodiesterase mRNA splicing and degradation. Mol Cell Biol. 2015;35:1223–37. doi: 10.1128/MCB.00993-14.PubMedPubMedCentralCrossRefGoogle Scholar
  57. Lukas M, Neumann ID. Oxytocin and vasopressin in rodent behaviors related to social dysfunctions in autism spectrum disorders. Behav Brain Res. 2013;251:85–94. doi: 10.1016/j.bbr.2012.08.011.PubMedCrossRefPubMedCentralGoogle Scholar
  58. Luo HR, Wu GS, Dong C, Arcos-Burgos M, Ribeiro L, Licinio J, et al. Association of PDE11A global haplotype with major depression and antidepressant drug response. Neuropsychiatr Dis Treat. 2009;5:163–70.PubMedPubMedCentralGoogle Scholar
  59. Maes M, Bosmans E, Calabrese J, Smith R, Meltzer HY. Interleukin-2 and interleukin-6 in schizophrenia and mania: effects of neuroleptics and mood stabilizers. J Psychiatr Res. 1995;29:141–52.PubMedCrossRefGoogle Scholar
  60. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E, Neels H. Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine. 1997;9:853–8. doi: 10.1006/cyto.1997.0238.PubMedCrossRefPubMedCentralGoogle Scholar
  61. Makhlouf A, Kshirsagar A, Niederberger C. Phosphodiesterase 11: a brief review of structure, expression and function. Int J Impot Res. 2006;18:501–9. doi: 10.1038/sj.ijir.3901441.PubMedCrossRefPubMedCentralGoogle Scholar
  62. Malhi GS, Tanious M, Das P, Coulston CM, Berk M. Potential mechanisms of action of lithium in bipolar disorder. Current understanding. CNS Drugs. 2013;27:135–53. doi: 10.1007/s40263-013-0039-0.PubMedCrossRefPubMedCentralGoogle Scholar
  63. Marquis JP, Goulet S, Dore FY. Neonatal ventral hippocampus lesions disrupt extra-dimensional shift and alter dendritic spine density in the medial prefrontal cortex of juvenile rats. Neurobiol Learn Mem. 2008;90:339–46. doi: 10.1016/j.nlm.2008.04.005.PubMedCrossRefPubMedCentralGoogle Scholar
  64. Matthiesen K, Nielsen J. Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity. Biochem J. 2009;423:401–9. doi: 10.1042/BJ20090982.PubMedCrossRefPubMedCentralGoogle Scholar
  65. Mertens J, Wang QW, Kim Y, Yu DX, Pham S, Yang B, et al. Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder. Nature. 2015;527:95–9. doi: 10.1038/nature15526.PubMedPubMedCentralCrossRefGoogle Scholar
  66. Mirabello L, Kratz CP, Savage SA, Greene MH. Promoter methylation of candidate genes associated with familial testicular cancer. Int J Mol Epidemiol Genet. 2012;3:213–27.PubMedPubMedCentralGoogle Scholar
  67. Mori S, Tardito D, Dorigo A, Zanardi R, Smeraldi E, Racagni G, et al. Effects of lithium on cAMP-dependent protein kinase in rat brain. Neuropsychopharmacology. 1998;19:233–40. doi: 10.1016/S0893-133X(98)00018-9.PubMedCrossRefPubMedCentralGoogle Scholar
  68. Moser MB, Moser EI. Functional differentiation in the hippocampus. Hippocampus. 1998;8:608–19.PubMedCrossRefGoogle Scholar
  69. Neves SR, Ram PT, Iyengar R. G protein pathways. Science. 2002;296:1636–9. doi: 10.1126/science.1071550.PubMedCrossRefPubMedCentralGoogle Scholar
  70. Niculescu AB, Levey DF, Phalen PL, Le-Niculescu H, Dainton HD, Jain N, et al. Understanding and predicting suicidality using a combined genomic and clinical risk assessment approach. Mol Psychiatry. 2015. doi: 10.1038/mp.2015.112.
  71. Oki NO, Motsinger-Reif AA, Antas PR, Levy S, Holland SM, Sterling TR. Novel human genetic variants associated with extrapulmonary tuberculosis: a pilot genome wide association study. BMC Res Notes. 2011;4:28. doi: 10.1186/1756-0500-4-28.PubMedPubMedCentralCrossRefGoogle Scholar
  72. Papatheodoropoulos C, Kostopoulos G. Dorsal-ventral differentiation of short-term synaptic plasticity in rat CA1 hippocampal region. Neurosci Lett. 2000;286:57–60.PubMedCrossRefGoogle Scholar
  73. Pathak A, Stewart DR, Faucz FR, Xekouki P, Bass S, Vogt A, et al. Rare inactivating PDE11A variants associated with testicular germ cell tumors. Endocr Relat Cancer. 2015;22:909–17. doi: 10.1530/ERC-15-0034.PubMedCrossRefPubMedCentralGoogle Scholar
  74. Pathak G, Agostino MJ, Bishara K, Capell WR, Fisher JL, Hegde S, et al. PDE11A negatively regulates lithium responsivity. Mol Psychiatry. 2016. doi: 10.1038/mp.2016.155.
  75. Perlis RH, Fijal B, Dharia S, Heinloth AN, Houston JP. Failure to replicate genetic associations with antidepressant treatment response in duloxetine-treated patients. Biol Psychiatry. 2010;67:1110–3. doi: 10.1016/j.biopsych.2009.12.010.PubMedCrossRefPubMedCentralGoogle Scholar
  76. Peverelli E, Ermetici F, Filopanti M, Elli FM, Ronchi CL, Mantovani G, et al. Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients. Eur J Endocrinol/Eur Fed Endocr Soc. 2009;161:687–94. doi: 10.1530/EJE-09-0677.CrossRefGoogle Scholar
  77. Rahman S, Li PP, Young LT, Kofman O, Kish SJ, Warsh JJ. Reduced [3H]cyclic AMP binding in postmortem brain from subjects with bipolar affective disorder. J Neurochem. 1997;68:297–304.PubMedCrossRefGoogle Scholar
  78. Roman F, Soumireu-Mourat B. Behavioral dissociation of anterodorsal and posteroventral hippocampus by subseizure stimulation in mice. Brain Res. 1988;443:149–58.PubMedCrossRefGoogle Scholar
  79. Schreiber G, Avissar S. Lithium sensitive G protein hyperfunction: a dynamic model for the pathogenesis of bipolar affective disorder. Med Hypotheses. 1991;35:237–43.PubMedCrossRefGoogle Scholar
  80. Schreiber G, Avissar S, Danon A, Belmaker RH. Hyperfunctional G proteins in mononuclear leukocytes of patients with mania. Biol Psychiatry. 1991;29:273–80.PubMedCrossRefGoogle Scholar
  81. Simon NM, McNamara K, Chow CW, Maser RS, Papakostas GI, Pollack MH, et al. A detailed examination of cytokine abnormalities in major depressive disorder. Eur Neuropsychopharmacol. 2008;18:230–3. doi: 10.1016/j.euroneuro.2007.06.004.PubMedCrossRefPubMedCentralGoogle Scholar
  82. Stoesz BM, Hare JF, Snow WM. Neurophysiological mechanisms underlying affiliative social behavior: insights from comparative research. Neurosci Biobehav Rev. 2013;37:123–32. doi: 10.1016/j.neubiorev.2012.11.007.PubMedCrossRefPubMedCentralGoogle Scholar
  83. Sun X, Young LT, Wang JF, Grof P, Turecki G, Rouleau GA, et al. Identification of lithium-regulated genes in cultured lymphoblasts of lithium responsive subjects with bipolar disorder. Neuropsychopharmacology. 2004;29:799–804. doi: 10.1038/sj.npp.1300383.PubMedCrossRefPubMedCentralGoogle Scholar
  84. Tipton LA, Christensen L, Blacher J. Friendship quality in adolescents with and without an intellectual disability. J Appl Res Intellect Disabil. 2013;26:522–32. doi: 10.1111/jar.12051.PubMedPubMedCentralGoogle Scholar
  85. Tseng KY, Lewis BL, Hashimoto T, Sesack SR, Kloc M, Lewis DA, et al. A neonatal ventral hippocampal lesion causes functional deficits in adult prefrontal cortical interneurons. J Neurosci. 2008;28:12691–9. doi: 10.1523/JNEUROSCI.4166-08.2008.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Vezzosi D, Libe R, Baudry C, Rizk-Rabin M, Horvath A, Levy I, et al. Phosphodiesterase 11A (PDE11A) gene defects in patients with acth-independent macronodular adrenal hyperplasia (AIMAH): functional variants may contribute to genetic susceptibility of bilateral adrenal tumors. J Clin Endocrinol Metab. 2012;97:E2063–9. doi: 10.1210/jc.2012-2275.PubMedPubMedCentralCrossRefGoogle Scholar
  87. Viero C, Shibuya I, Kitamura N, Verkhratsky A, Fujihara H, Katoh A, et al. REVIEW: oxytocin: crossing the bridge between basic science and pharmacotherapy. CNS Neurosci Ther. 2010;16:e138–56. doi: 10.1111/j.1755-5949.2010.00185.x.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Watanabe S, Iga J, Nishi A, Numata S, Kinoshita M, Kikuchi K, et al. Microarray analysis of global gene expression in leukocytes following lithium treatment. Hum Psychopharmacol. 2014;29:190–8. doi: 10.1002/hup.2381.PubMedCrossRefPubMedCentralGoogle Scholar
  89. Weeks 2nd JL, Zoraghi R, Francis SH, Corbin JD. N-terminal domain of phosphodiesterase-11A4 (PDE11A4) decreases affinity of the catalytic site for substrates and tadalafil, and is involved in oligomerization. Biochemistry. 2007;46:10353–64. doi: 10.1021/bi7009629.PubMedCrossRefPubMedCentralGoogle Scholar
  90. Weeks 2nd JL, Corbin JD, Francis SH. Interactions between cyclic nucleotide phosphodiesterase 11 catalytic site and substrates or tadalafil and role of a critical Gln-869 hydrogen bond. J Pharmacol Exp Ther. 2009;331:133–41. doi: 10.1124/jpet.109.156935.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Witwicka H, Kobialka M, Siednienko J, Mitkiewicz M, Gorczyca WA. Expression and activity of cGMP-dependent phosphodiesterases is up-regulated by lipopolysaccharide (LPS) in rat peritoneal macrophages. Biochim Biophys Acta. 2007;1773:209–18. doi: 10.1016/j.bbamcr.2006.10.008.PubMedCrossRefPubMedCentralGoogle Scholar
  92. Wong ML, Whelan F, Deloukas P, Whittaker P, Delgado M, Cantor RM, et al. Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response. Proc Natl Acad Sci U S A. 2006;103:15124–9.PubMedPubMedCentralCrossRefGoogle Scholar
  93. Xu Y, Zhang HT, O’Donnell JM. Phosphodiesterases in the central nervous system: implications in mood and cognitive disorders. Handb Exp Pharmacol. 2011;447–85. doi: 10.1007/978-3-642-17969-3_19.
  94. Yuasa K, Kotera J, Fujishige K, Michibata H, Sasaki T, Omori K. Isolation and characterization of two novel phosphodiesterase PDE11A variants showing unique structure and tissue-specific expression. J Biol Chem. 2000;275:31469–79. doi: 10.1074/jbc.M003041200.PubMedCrossRefPubMedCentralGoogle Scholar
  95. Yuasa K, Kanoh Y, Okumura K, Omori K. Genomic organization of the human phosphodiesterase PDE11A gene. Evolutionary relatedness with other PDEs containing GAF domains. Eur J Biochem/FEBS. 2001a;268:168–78.CrossRefGoogle Scholar
  96. Yuasa K, Ohgaru T, Asahina M, Omori K. Identification of rat cyclic nucleotide phosphodiesterase 11A (PDE11A): comparison of rat and human PDE11A splicing variants. Eur J Biochem/FEBS. 2001b;268:4440–8.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, Physiology and NeuroscienceUniversity of South Carolina School of MedicineColumbiaUSA