Located on chromosome 4q31.1 in humans, the gene NR3C2 encodes the mineralocorticoid receptor (Fan et al. 1989; Morrison et al. 1990). It has 5201 bp, an exon count of 12, and is located on chromosome 8 in mice, 19 in rats, 1 in zebra fish, and 4 in chickens. Mineralocorticoids (MRs) belong to the nuclear receptor subfamily 3 and are distributed throughout the epithelia of the kidneys, sweat glands, and colon and the nonepithelial tissues of the heart and brain. The human MR was first cloned in 1987, consists of 984 amino acids, and is similar in structure to the glucocorticoid receptor, sharing 94% identity in the DNA-binding domain (Funder 1997).
It is unique among steroid receptors in that it plays signaling roles in both mineralocorticoids (e.g., aldosterone and deoxycorticosterone) and the glucocorticoids (cortisol in humans, corticosterone in rats). In particular, both cortisol and corticosterone bind to MR with similar affinity as aldosterone, but aldosterone will only bind to glucocorticoid (GR) at very high concentrations. This was determined through structural studies that showed that despite both MR and GR showing high sequence homology in their ligand-binding domains (Sturm et al. 2005), nonspecific amino acid interactions between sequences 804–844 were identified as essential for aldosterone specificity (Rogerson et al. 1999). NR3C2 defects may result in autosomal dominant pseudohypoaldosteronism type I. This disorder characteristically entails a high flow rate of very dilute urine. Other gene mutations may result in early-onset hypertension severely exacerbated in pregnancy.
MR is expressed in many cells in the body, where it modulates ion and fluid balance, response to injury, and early responses to stress. Given the ubiquitous nature of MR, this encyclopedia chapter focuses on the role of MR as a signaling molecule in the brain. For recent general information on MR, the reader is directed to a 2014 review by Gomez-Sanchez (Gomez-Sanchez and Gomez-Sanchez 2014).
MR Signaling in the Brain
The body’s ability to adapt to stress requires the facilitation of neuronal plasticity mediated by cortisol (in humans) and corticosterone (in rodents) (Sarabdjitsingh and Joels 2014). Cortisol binds to genomic receptors such as the mineralocorticoid (MR) and glucocorticoid (GR) receptors which function as transcription factors and permit stress-related information to be stored for subsequent use (Prager and Johnson 2009). The receptors regulate a variety of gene transcriptional processes including the synthesis of new proteins which facilitate synaptic plasticity (Prager and Johnson 2009). These processes are modulated by binding of steroids, including cortisol (corticosterone in rodents) to both MRs and GRs. Cortisol binds with higher affinity to MR than to GR (Prager and Johnson 2009; Joels et al. 2012; de Kloet 2014).
Localization of MR in the Brain and Body
MRs are distributed throughout the tissues of the brain, heart, kidney, colon, hippocampus, hypothalamus, and adrenal fasciculata. Subcellular locations include the cytoplasm, nucleus, endoplasmic reticulum membrane, and plasma membrane. Epithelial locations include parts of the nephron (distally), the colon (distally), and sweat and salivary glands. Nonepithelial loci include the neurons of the central nervous system, cardiac myocytes, and smooth muscle cells of large vessels such as the aorta.
MRs are predominantly expressed in the learning and memory centers of the brain such as the hippocampus and amygdala (Reul and Kloet 1985). Localized in the membrane, they facilitate second messenger (e.g., G protein) cascades to directly affect membrane proteins, including the regulation of membrane potential through gated ion channels (Prager and Johnson 2009; Prager et al. 2010; Joels et al. 2012). Electron microscopy studies have shown MRs expressed at nuclear locations within the lateral amygdala on glutamatergic (excitatory) and GABAergic (inhibitory) neurons and at the extranuclear loci of presynaptic terminals, dendrites, and their spines (Prager et al. 2010). Electron microscopy has allowed identification of MRs localized to Golgi apparatus and mitochondrial membranes (Johnson et al. 2005; Prager et al. 2010).
Function of MR in the Brain and Body
Conditioned fear can coexist with or trigger the stress response, elevating adrenal hormones in the brain. Amygdala-dependent activation of the hypothalamic-pituitary-adrenal (HPA) axis facilitates expression of conditioned fear. The HPA axis increases corticosterone blood concentrations which facilitates binding to MRs and GRs within the limbic system. In the brain genomic MRs (gMRs) have high-affinity binding with glucocorticoids (e.g., cortisol, corticosterone), mineralocorticoids (e.g., aldosterone), and progesterone (Krozowski and Funder 1983). The diverse distribution of MRs implicates mineralocorticoid effects on neuronal function in specific subregions of the brain. The lateral nucleus of the amygdala, which both acquires and stores fear memories, is the primary site for the resultant synaptic plasticity (Prager et al. 2010). Studies of chronic stress models have shown hypertrophy of dendrites in amygdala principal neurons (Johnson et al. 2005).
In epithelial tissues aldosterone activates MRs, by converting cortisol to NAD and NADH. This facilitates protein expression which regulates the epithelial sodium channel, sodium potassium pump, and serum- and glucocorticoid-induced kinase. Sodium and water are reabsorbed resulting in increased extracellular volume, increased blood pressure, and reduced potassium levels due to potassium excretion (to maintain homeostasis).
Cortisol Signaling to Intracellular Genomic MR (gMR)
During stress corticosterone enters the brain rapidly, binding to MRs in the limbic brain regions such as the septum, hippocampus, and amygdala. In the hippocampus, the receptors bind to a complex of heat shock proteins (e.g., HSP90, 70, 56, etc.) and, once activated, dissociate from these proteins to homodimerize with other receptors (Rupprecht et al. 1993). The dimerized genomic MRs translocate to the nucleus of the cell and bind to mineralocorticoid response element (MRE), which modulates gene transcription into mRNA of the activated genes. MRE is a short DNA dimer, denoted by a pair of inverted repeats that are partitioned by three nucleotides. Located within the promoter of a gene, it specifically binds a steroid hormone receptor complex in order to regulate transcription. MRs at postsynaptic membrane densities of excitatory synapses have been shown to regulate synaptic transmission (Prager et al. 2010).
Structure of MR
The MR adopts a quaternary structure and is comprised of three domains: the N-terminal domain, a DNA-binding domain, and a C-terminal ligand-binding domain (Pawlak et al. 2012) In the absence of a ligand, MR will form a heteromultimeric cytoplasmic complex with heat shock proteins HSP90, HSP70, and FKBP4 (Bruner et al. 1996) In the presence of a ligand, after binding, it translocates to the nucleus to bind to DNA as a homodimer and as a heterodimer with NR3C1.
Cortisol Signaling to Membrane-Localized MR (mMR)
Like the closely related GR, MR has also been identified as a functional membrane receptor (mMR). In neurons mMR are fast-acting receptors that have been documented to regulate synaptic transmission (for review see Prager and Johnson 2009; Joels et al. 2012; Russo et al. 2016). Anatomical evidence for their existence was recently documented using electron microscopy where possible mMR where found in postsynaptic densities as well as presynaptic structures (Prager et al. 2010). Functional evidence for a rapid signaling membrane-based MR has been documented by extensive electrophysiological studies by Joels and colleagues; see Joels et al. for review (Joels et al. 2012). In a classic study of fast-signaling actions, MR agonists were found to facilitate presynaptic glutamate release (Karst et al. 2005).
Pharmacology of MR
The endogenous ligands of MR in order of potency are corticosterone, cortisol, aldosterone, and progesterone. Nuclear MR binds with high affinity to corticosterone and cortisol (Reul and Kloet 1985). Due to GR lower-binding affinity, its genomic response occurs only after exposure to a stressful event (Joels 2008). The rate of occupancy and activation of MR is comprehensive even when circulating hormone levels are low, pointing to a role for MRs in variations of ultradian rhythm (Russo et al. 2016). mMRs were found to regulate ion channels to moderate the speed of neuronal depolarization and synaptic transmission (Prager and Johnson 2009). Presynaptic calcium levels increased glutamate release in the hippocampus, while the postsynaptic efflux of potassium was inhibited, reducing hyperpolarization (Prager and Johnson 2009).
Apart from cortisol, agonists of MR include aldosterone, produced in the adrenal glands, that acts on the renin-angiotensin system; prednisolone and dexamethasone, both anti-inflammatories; and progesterone, a sex hormone and fludrocortisone, used to treat cerebral salt-wasting syndrome. MR antagonists include spironolactone, a diuretic to prevent salt absorption and potassium excretion, eplerenone an antihypertensive, finerenone used in the treatment of chronic heart failure, and onapristone for the treatment of breast cancer.
When presented with stressful situations, corticosteroids are released effecting the brain and, as a consequence, behavior. Both MR and GR mediate these actions through their expression on neurons within the limbic system, but MR has a much higher binding affinity to the naturally occurring cortisol and therefore does not require the introduction of stress to become active. MR plays a major role in the regulation of ion and water transport via the renin-angiotensin system. Gene mutations are linked with autosomal dominant pseudohypoaldosteronism type I and pregnancy-exacerbated hypertension. Alternate splicing can result in multiple transcript variants.
MR moderates ligand-dependent transcription and binds to MRE to transactivate specific target genes. The high-affinity binding of cortisol to MRs lends credence to the nongenomic effects of mMRs to induce fast responses in neuronal second messenger systems to regulate synaptic transmission (Prager et al. 2010). The mineralocorticoid receptor-binding properties, interactions with other genes, and extensive tissue expression afford its great functional diversity and multifarious physiological regulation.
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