Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

G alpha o

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101497

Synonyms

 Gαo;  Gαo1;  Gαo2;  GNAO1

Historical Background

Heterotrimeric G proteins, consisting of the three subunits α, β, and γ, belong to a family of guanine nucleotide-binding proteins that are involved as transducers in various transmembrane signaling systems. Gs and Gi proteins are involved in the hormonal regulation of adenylate cyclase activity. Gs activates cyclase in response to β-adrenergic stimuli, whereas the Gi protein mediates the inhibition of cyclase (Hepler and Gilman 1992). Bordetella pertussis toxin (PTX) was isolated as the islet-activating protein by Ui and his colleagues. PTX mediates the ADP ribosylation of Gi proteins (Katada and Ui 1982). The Go protein was isolated during the purification of Gi proteins from bovine brain for use as the substrate for PTX-mediated ADP ribosylation and was named the “other” G protein. The Go protein contains three subunits with molecular weights of 39 kDa (α subunit), 36 kDa (β subunit), and 8 kDa (γ subunit). The first cDNA clone of Gαo was isolated by screening a rat glioma cDNA library (Itoh et al. 1986). Species orthologs of the Gαo protein are highly conserved, with 83% identity of amino acid sequences in Drosophila melanogaster and 82% identity of those in Caenorhabditis elegans with those in Homo sapiens.

There are two primary splice variants, the Gαo1 and Gαo2 proteins. The amino acids encoded in the first six exons are common to both Gαo proteins, but the remainder of the two proteins are encoded by two different pairs of exons that are selected through alternative splicing. This unusual gene organization may have been derived from a pair of tandemly duplicated genes. The different splice forms encode proteins that were shown to be functionally distinct. The inhibition of voltage-dependent Ca2+ channels in secretory cells by plasma membrane receptors is mediated by PTX-sensitive G proteins. M4-AChR receptors are coupled with Go1 (α1β3γ4), whereas SSR2 receptors are coupled with Go2 (α2β1γ3), as demonstrated by the microinjection of antisense oligonucleotides into GH3 cells.

Function

Go is the most abundant G protein in the central and peripheral nervous systems, where it comprises about 1% of membrane proteins in mammalian brains. The Go protein is activated not only by many neurotransmitters and hormone G protein-coupled receptors (GPCRs) but also by a growth cone-associated protein with a molecular weight of 43 kDa (GAP-43) (Jiang and Bajpayee 2009; Kasahara and Ui 2011).

In the neuronal growth cone, Go makes up 10% of membrane proteins. GAP-43 is a neuronal protein associated with the cytosolic face of the growth cone plasma membrane and enhances guanosine diphosphate (GDP) release, guanosine triphosphate (GTP) binding, and the guanosine triphosphatase (GTPase) activity of the Go protein. Transfection of an activated Gαo protein enhances neurite extension, suggesting that Go protein signaling is utilized in neuronal outgrowth during development and axonal regeneration. Endocannabinoid-Gαo signaling inhibits postdevelopmental axonal regeneration in C. elegans.

Go has been shown to play a role in visual signal transduction. Retinal bipolar cells are interneurons that receive glutamatergic inputs from photoreceptors. Visual information is segregated into two types of bipolar neuron, ON and OFF neurons. Glutamate released onto retinal ON bipolar neurons binds to metabotropic glutamate receptor 6 (mGluR6), to activate Go1 (Dhingra et al. 2002). A splice variant Gαo2 plays a role in improving the sensitivity of rod bipolar cells through its action with Gαo1.

Go has also been shown to play a role in olfactory reception. The Go protein is expressed in odorant receptor neurons of D. melanogaster antennae. Go is the only PTX-sensitive G protein in D. melanogaster; therefore, PTX selectively inhibits Go signaling. PTX expression in olfactory receptor neurons decreases the amplitude and enhances the termination of electroantennogram responses, thereby decreasing odor-induced spike frequency in individual odorant receptor neurons (Chatterjee et al. 2009).

Go also has a role in memory and learning in D. melanogaster. Induction of PTX within mushroom body neurons leads to impaired appetitive and aversive memory acquisition without affecting memory stability.

Furthermore, Go plays a role in sweet taste perception in D. melanogaster. Gαo is involved in the detection of sucrose, glucose, and fructose, but not trehalose and maltose. Gαo is also involved in the detection of the plant toxin L-canavanine by DmXR, a variant GPCR, in bitter-sensitive taste neurons of D. melanogaster (Devambez et al. 2013).

Go protein signaling has also been implicated in heart contractility. The Go protein is preferentially expressed in atrial endocrine cardiomyocytes and peripheral neurons. Enhanced calcium cycling and contractile function are observed in transgenic hearts expressing a constitutively active Gαo protein. Muscarinic receptor-mediated cardiac parasympathetic activity is essential for the regulation of heart rate and heart rate variability, and the Go protein is involved in this regulation.

The frizzled (Fz) receptor belongs to the superfamily of GPCRs and transduces important signals during animal development. In D. melanogaster, the Fz receptor mediates two distinct transduction pathways: the Wnt and planar polarity pathways. The Gαo protein is required for the transduction of both pathways (Katanaev et al. 2005). The Go protein transduces signals from the Fz receptor, which directs the asymmetric distribution of effectors and establishes the axis for cell polarization. Gαo links Wnt-Fz signaling with ankyrins to regulate the neuronal microtubule cytoskeleton for neuromuscular junction formation. The Gαo-ankyrin interaction is conserved in the mammalian neurite outgrowth pathway.

C. elegans enters an alternative developmental stage called dauer under unfavorable conditions such as starvation. DAF-7/TGFβ is an important ligand in this signaling pathway. Gαo regulates daf-7 expression during larval development. In addition, the normal daf-7 response to starvation is altered in Gαo mutants.

Regulation of Activity

The Gαo protein is a Gi class α subunit of the heterotrimeric G protein family. It is activated by heptahelical cell-surface receptors called GPCRs. Activated GPCRs promote the exchange of GDP for GTP on the Gαo protein, causing a conformational change, which possibly involves G protein βγ (Gβγ) disassociation and Gαo activation. The Gβγ subunits constitute an anchorage point on the plasma membrane and assist in coupling the G protein to its appropriate receptors. The Gαo protein has intrinsic GTPase activity, which returns to an inactivated state by hydrolysis of GTP to yield GDP.

Activation

The activation of the Gαo protein by GPCRs follows the same steps as in all G proteins: an agonist binds to the extracellular surface of a GPCR and induces a conformational change that leads to G protein activation. GPCRs that interact with Gαo are those for neurotransmitters (Table 1). AGS-3, a protein containing the G protein regulator domain, activates Gαo in ASH chemosensory neurons to allow food-deprived C. elegans to delay response to aversive stimuli (Hofler and Koelle 2011).
G alpha o, Table 1

Go-coupled receptors

Go-coupled receptors

References

Adenosine A1 receptor

J Neurochem 64(5) 2034-42 (1995)

α2A adrenergic receptor

Proc Natl Acad Sci U S A 102(51) 18706-11 (2005)

γ-aminobutyric acid B

FEBS Lett 271(1-2) 231-5 (1990)

Chemokine (C-X-C motif) receptor 4

J Biol Chem 282(36) 26392-400 (2007)

Corticotropin-releasing factor 2 Receptor

Cell Signal 21(9) 1436-43 (2009)

D2 dopamine receptors

Proc Natl Acad Sci U S A 98(6) 3577-82 (2001)

Egg-laying-defectice mutant EGL-6

Nat Neurosci 11(10) 1168-76 (2008)

Egg-laying-defectice mutant EGL-47

J Neurosci 24(39) 8522-30 (2004)

Galanin receptor

EMBO J 14(19)4728-37 (1995)

5-hydroxytryptamine 1P receptor

J Pharmacol Exp Ther 277(1) 518-24 (1996)

Muscarinic acetylcholine receptor M2

FEBS J 273(24) 5508-5516 (2006)

Muscarinic acetylcholine receptor M4

Nature 353(6339) 43-8 (1991)

Neuromedin U receptor 1

J Biol Chem 287(22) 18562-72 (2012)

Neuropeptide Y receptor

Proc Natl Acad Sci U S A 85(10) 3633-7 (1988)

δ-opioid receptor

J Neurochem 86(5) 1213-22 (2003)

μ-opioid receptor

Proc Natl Acad Sci U S A 85(18) 7013-7 (1988)

Opioid receptor-like 1 receptor

Protein Pept Lett 13(5) 437-41 (2006)

P2Y2 nucleotide receptor

J Biol Chem 280(47) 39050-7 (2005)

Somatostatin receptor

J Biol Chem 268(15) 10721-7 (1993)

Deactivation

Regulators of G protein signaling (RGS) proteins negatively regulate G protein signaling through the acceleration of GTP hydrolysis by Gα. RGS1, 4, 7, 11, 14, 16, 19 (also known as Gα-interacting protein (GAIP)), 20 (also known as Ret RGS), and egl-10 have been shown to physically interact with the Gαo protein. A member of the R7 RGS family, RGS11, is specifically expressed in retinal ON bipolar cells, where it forms a complex with the atypical G protein β subunit 5 (Gβ5) and RGS9 anchor protein (R9AP). Association with R9AP has been shown to stimulate the GTPase-activating activity of the RGS11/Gβ5 complex at Gαo. In neurons of the striatum, RGS7/Gβ5 selectively serves as a GTPase-accelerating protein for Gαo (Masuho et al. 2013). In a Xenopus oocyte, RGS4 and Gαo regulate GPCR-coupled potassium ion channel deactivation. RGS protein EGL-10 and Gαo modulate the response of C. elegans ASH polymodal nociceptive sensory neurons to repellents. The crystal structure of the Gαo protein bound to RGS suggests the existence of unique structural determinants specific to particular RGS protein-Gα pairings. These negative regulators of the Gαo protein may provide a cell-specific mechanism for Gαo-regulated signaling pathways. PTX catalyzes the ADP-ribosylation of the α subunits of the Go, Gi, and Gt proteins at the C-terminal cysteine residue (−4 position). This prevents the G protein from interacting with GPCRs on the cell membrane, thus interfering with intracellular signaling.

Interaction with Effectors

The Gαo protein regulates several intracellular effectors and interaction partners in their functional signaling pathways (Table 2). An activated Gαo protein can interact directly with many types of ion channel to induce the regulation of signaling pathways.
G alpha o, Table 2

Go-interaction partners

Go-interaction partners

References

Ankyrin

Development 141(17) 3399-409 (2014)

Axin

Dev Dyn 239(1) 168-83 (2010)

GRIN1

Mol Pharmacol 67(3) 695-702 (2005)

Guanylate cyclase

Brain Res 1144 42-51 (2007)

Inwardly-rectifying potassium channel

Science 242(4884) 1433-7 (1988)

Kermit

PLoS ONE 8(10) e76885 (2013)

P/Q-type Ca2+ channel α1A subunit

J Biol Chem 276(31) 28731-8 (2001)

L-type Ca2+ channel

Proc Natl Acad Sci U S A 94(5) 1727-32 (1997)

N-type Ca2+ channel

Proc Natl Acad Sci U S A 95(6) 3269-74 (1998)

Na+ channel α subunit

J Biol Chem 274(11) 7431-40 (1999)

Necdin

Cell Commun Signal 12 39 (2014)

Pins

Mol Biol Cell 20(17) 3865-77 (2009)

Promyelocytic leukemia zinc finger protein

Cell Signal 20(5) 884-91 (2008)

Rab5

Sci Signal 3(136) ra65 (2010)

Rap1 GTP-ase activating protein (Rap1GAP)

J Biol Chem 274(31) 21507-10 (1999)

Small GTPase Ras-like without CAAX 1

Neuroreport 19(5) 521-5 (2008)

TRPM1

Sci Rep 6 20940 (2016)

TRPM1-L

Proc Natl Acad Sci U S A 107(1) 332-7 (2010)

Tublin

J Biol Chem 274(19) 13485-90 (1999)

The regulation of neurotransmitter release at presynaptic terminals is an important mechanism underlying the modulation of synaptic transmission in the nervous system. Inhibitory regulation of neurotransmitter release is mediated by various GPCRs such as the α2 adrenergic receptor, μ-opioid receptor, δ-opioid receptor, GABAB receptor, and adenosine A1 receptor. A major mechanism by which the Gαo protein mediates the inhibition of transmitter release is the inhibitory modulation of the action potential-evoked N-type Ca2+ entry to presynaptic terminals, which is required to trigger transmitter release.

The Gαo protein associates with many ion channels, neurotransmitter GPCRs, GAP-43, and APP, indicating that the Gαo protein possesses various neurological functions in the body.

Subcellular Localization

The Gαo protein is primarily targeted to the cytoplasmic face of the plasma membrane. Glycine at the N-terminus (Gly2) is myristoylated. Cysteine at the N-terminus (Cys3) is palmitoylated, although myristoylation is a prerequisite to palmitoylation. Palmitoylation is markedly reduced by extracellular signals, suggesting that the palmitoylation of the Gαo protein is dynamic and highly regulated. The plasma membrane targeting of the Gα protein is considered to require both interaction with the βγ complex and the subsequent palmitoylation of the Gα protein at the Golgi apparatus. The regulatory mechanism of palmitoylation by extracellular signals remains to be explored.

Lipid rafts are considered to be subdomains of the plasma membrane that contain high concentrations of cholesterol and glycosphingolipids. The lipid composition renders the rafts resistant to solubilization by nonionic detergents. The Gαo protein, but not the Gαi2 and Gαi3 proteins, undergoes activation-dependent translocation into detergent-resistant membrane rafts of the rat cerebellum (Yuyama et al. 2007a). Most heterotrimeric Go protein exists in the non-raft fraction in the adult rat cerebellum. Gαo undergoes translocation to the lipid rafts in the early stage of cerebellar development. Treatment with stromal cell-derived factor 1α, a physiological ligand for the GPCR, stimulated GTPγS binding to Gαo and caused Gαo translocation to the lipid rafts, leading to the growth cone collapse of cerebellar granule neurons. This translocation may be induced by both the dual saturated acylation (myristoylation and palmitoylation) of the Gαo protein and the interaction of the Gαo protein with the raft-resident protein GAP-43. The linkage of Gγ to prenyl residues, which contain unsaturated bonds, is considered to facilitate the exclusion from the lipid rafts. Therefore, activation-dependent translocation may be a consequence of the dissociation of the heterotrimeric G protein (Fig. 1). Furthermore, the Gαo protein, but not the Gαi2 and Gαi3 proteins, is associated with raft-resident GAP-43 only after treatment with guanosine 5′-O-(3-thiotriphosphate) (GTPγS), but not guanosine 5′-O-(2-thiodiphosphate) (GDPβS) (Yuyama et al. 2007a). A large number of GPCRs have been shown to be abundant in membrane rafts, depending on the cell type examined. Several effectors including adenylate cyclase, GRIN1, and tubulin have also been reported to be present in membrane rafts.
G alpha o, Fig. 1

Model of activation-dependent translocation of Gαo to lipid rafts. Most heterotrimeric Go protein exists in the non-raft fraction in the adult rat cerebellum (upper). Gαo undergoes translocation to the lipid rafts (red domain) in the early stage of cerebellar development (lower)

Spatial colocalization is a possible determinant of the fidelity of GPCR-heterotrimeric G protein coupling. Lipid rafts may increase efficiency by concentration of GPCRs, heterotrimeric G protein, and effectors on both sides of the plasma membrane and enhance specificity by selectively segregating them (Yuyama et al. 2007b).

Disease

Gαo is a molecular switch that controls signal transduction, and its dysregulation can promote oncogenesis. Somatic mutations in the GNAO1 gene induce oncogenesis by rendering Gαo constitutively activated. Several somatic mutations in Gαo have been identified in human cancers (Kan et al. 2010). The somatic mutation arginine 243→histidine (R243H) in Gαo was identified in breast carcinoma. R243H mutation renders Gαo constitutively active by accelerating the rate of nucleotide exchange and enhances Src-STAT3 signaling in NIH-3T3 cells, a pathway shown to be triggered by active Gαo proteins to promote cellular transformation (Garcia-Marcos et al. 2011). Expression of the constitutively active Q205L Gαo that lacks GTPase activity in NIH 3T3 cells results in STAT3-mediated transformation. Furthermore, pathological estrogen receptor α signaling is the primary growth cascade in breast cancer. Gαo potentiates estrogen receptor α activity via the ERK signaling pathway. GNAO1 is overexpressed in gastric cancer, and its overexpression correlates with a poor prognosis, as it promotes gastric cancer cell viability. The median survival rates of patients with a negative and a positive expression of Gαo are 61 and 27 months, respectively (P = 0.033).

De novo heterozygous mutations in the GNAO1 gene cause epileptic encephalopathy (Nakamura et al. 2013). By mapping the mutation onto three-dimensional models, three mutants (D174G, I279N, and T191-F197del) are predicted to destabilize the Gαo subunit fold. The G203R mutant is predicted to impair GTP binding and/or activation of downstream effectors. Cerebral atrophy and thin corpus callosum are common features. Patients with E246K and R209C mutations show movement disorder and intellectual disability with developmental delay. L199P mutation causes severe neurodevelopmental disorders, characterized by early infantile seizures, profound cognitive dysfunction, and occasionally movement disorder (early infantile epileptic encephalopathy-17, EIEE17).

Genome-wide association studies are a means to identify risk genes involved in human diseases. In such studies, one searches for the genome for small variations, called single-nucleotide polymorphisms, which occur more frequently in people with a particular disease than in people without the disease. SNPrs2126986 in an intron of GNAO1 is significantly associated with nonobstructive azoospermia in Han Chinese men (Qin et al. 2014).

Go may be involved in the pathogenesis of Alzheimer’s disease (AD). Neuronal degeneration is caused by senile plaques formed in AD. APP is the main component of senile plaques. The APP and presenilin 1 (PSEN1) genes have been identified as the causal factors for heritable familial AD. A physical interaction between APP and the Go protein has been demonstrated, and an APP familial AD mutant activates the Go protein. Analysis of the APP-Go protein interaction in human brain samples from AD patients at different stages revealed an attenuated interaction, which correlated with disease progression. Insect APP directly interacts with Gαo at synaptic terminals within the insect brain, and this interaction is regulated by Gαo activity. Perturbations affecting APP and Gαo signalings induce the same unique pattern of ectopic growth and migration, analogous to defective migration patterns seen in mice lacking APP family proteins.

Phenotype

Gαo-deficient mice exhibit hyperactive behavior, a unique clockwise turning behavior, and in some cases early death. They also show several neurological deficits including tremors, seizures, hyperalgesia (hot plate test), severe motor control impairment, olfactory behavior impairment, and death of accessory olfactory neurons. Gain-of-function knock-in mutant mice (GNAO1 +/G184S) rarely develop seizures and show a markedly increased frequency of interictal epileptiform discharges. This may be a mouse model, but it shows features that are commonly seen in EIEE17 syndrome of human epilepsy.

Opioid analgesics exert their effects via activation of the μ-opioid receptor, a G protein-coupled receptor that interacts with Go proteins. A reduction in the Gαo level in Gαo +/− heterozygous null mice attenuates the supraspinal antinociception induced by morphine. Morphine supraspinal antinociception is enhanced in a knock-in mouse that expresses an RGS-insensitive mutant Gαo protein, Gαo (G184S) (Lamberts et al. 2013). Chronic exposure to opioids leads to physical dependence, which manifests as the symptoms of drug withdrawal. The expression of Gαo in the locus coeruleus is upregulated in morphine-dependent C57BL/6J mice. Antisense knockdown of Gαo minimizes naloxone-precipitated withdrawal jumping in C57BL/6J mice. Gαo in the locus coeruleus contributes to interindividual variability in the physical dependence on opioids in mice. In Gαo2-deficient mice, cocaine-induced behavioral sensitization is abolished by disturbing the striatal dopamine system.

Muscarinic regulation of heart rate and heart rate variability is impaired in Gαo-deficient mice. These mice have a clear and specific defect in ion channel regulation in the heart. Normal muscarinic regulation of L-type calcium channels in ventricular myocytes is absent in mutant mice.

The rodent vomeronasal organ mediates the regulation of species-specific social behaviors. This organ consists of at least two distinct layers containing apical and basal populations of vomeronasal sensory neurons. Apical neurons express Gαi2 and the V1R family of vomeronasal GPCRs, whereas basal neurons express Gαo and members of the V2R receptor family. Gαo null mice exhibit reduced sensory responses of V2R receptor-expressing vomeronasal sensory neurons (Chamero et al. 2011).

D. melanogaster mutants with loss of function of Gαo show impaired morphogenesis of the heart and epithelial polarity of cardial cells. Such mutants show orientation and asymmetric division defects of sensory organ precursor cells. Loss-of-function somatic clones show defects in hair orientation and a strong multiple-wing-hair phenotype (Katanaev et al. 2005). Attenuating Go signaling in Drosophila pacemaker neurons by a PTX transgene lengthens the period of 24 h behavioral rhythms. In contrast, constitutive Go signaling induces arhythmicity in most flies. Therefore, Drosophila requires Go signaling to generate circadian behavior. The mushroom body has been highlighted as a sleep control center in fruit flies. Upregulation of Gαo in the mushroom body, the central brain region in Drosophila, promotes sleep, while inhibition of endogenous Go via expression of Gαo RNAi reduces sleep. Inhibition of Gαo activity in a restricted subtype of mushroom body neurons, i.e., the mushroom body α/β core neurons, leads to increased sleep (Yi et al. 2013).

In C. elegans, null mutations of goα-1 result in various phenotypes including a low frequency (11%) of embryonic lethality, partial sterility (Mendel et al. 1995), defects in neuronal migration, and increased levels of acetylcholine release from motor neurons. Gαo1 (loss-of-function) mutants display a number of behavioral defects including hyperactive locomotion and egg laying (Mendel et al. 1995), defects in sensory modulation of locomotion, and specific defects in male mating (Mendel et al. 1995). Selective removal of GNAO1 from the two hermaphrodite-specific neurons can sufficiently cause egg-laying defects. Gαo1 (loss-of-function) mutants are also resistant to the effects of volatile anesthetics.

Summary

Gαo is a pertussis toxin-sensitive Gi class α subunit of heterotrimeric G proteins. Gαo binds guanine nucleotides and has intrinsic guanosine triphosphatase (GTPase) activity. Similarly to all G protein α subunits, Gαo cycles between an inactive guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. It links activated G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Various GPCRs are coupled with Go. These include neurotransmitter receptors of biogenic amines, neuropeptides, and opioids. RGS proteins negatively regulate G protein signaling through the acceleration of GTP hydrolysis by Gα. RGS1, 4, 7, 11, 14, 16, 19, 20, and egl-10 have been shown to physically interact with the Gαo protein. Gαo regulates several intracellular effectors including ion channels, adenylate cyclase, guanylate cyclase, Rap1 GTPase-activating protein (Rap1GAP), axin, and pins. Compartmentalization of these signaling molecules in membrane rafts may ensure specificity and fidelity in Gαo signaling. Go is the most abundant G protein in the central nervous system, where it comprises about 1% of membrane proteins in the mammalian brain. Go regulates neuronal development, memory, visual reception, olfactory reception, and taste reception. It is also localized in heart tissue and implicated in heart contractility. Its expression is regulated during the development of the brain and heart. Somatic mutations in the GNAO1 gene induce human cancers by rendering Gαo constitutively activated. Heterozygous mutations in the GNAO1 gene cause epileptic encephalopathy by destabilizing Gαo. Gαo-deficient mice have several neurological deficits, including tremors, seizures, hyperalgesia, motor control impairment, and olfactory impairment. Muscarinic regulation of heart rate and heart rate variability is also impaired in Gαo-deficient mice. Drosophila melanogaster mutants with loss of function of Gαo show impaired morphogenesis of the heart and epithelial polarity of cardiac cells and abnormal sleep. Gαo-deficient C. elegans has phenotypes including neuronal migration defects, hyperactive locomotion, and egg laying.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratory of BiomembraneTokyo Metropolitan Institute of Medical ScienceTokyoJapan