Neurosteroids and GABA-A Receptor Function - PubMed (original) (raw)

Neurosteroids and GABA-A Receptor Function

Mingde Wang. Front Endocrinol (Lausanne). 2011.

Abstract

Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAA-receptor. 3α-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABA(A)-receptor in a non-genomic manner. Allopregnanolone (3α-OH-5α-pregnan-20-one), 5α-androstane-3α, 17α-diol (Adiol), and 3α5α-tetrahydrodeoxycorticosterone (3α5α-THDOC) enhance the GABA-mediated Cl(-) currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites. 3α5α-P and 3α5α-THDOC potentiate synaptic GABA(A)-receptor function and activate δ-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3β-OH pregnane steroids and pregnenolone sulfate (PS) are GABA(A)-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABA(A)-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABA(A)-receptor, mood changes, and cognitive functions.

Keywords: GABAA-receptor; THDOC; allopregnanolone; cognition; mood; pregnenolone sulfate; premenstrual dysphoric disorder.

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Figures

Figure 1

Figure 1

Biosynthesis of allopregnanolone and pregnenolone sulfate (PS) from cholesterol within the neuron or glial cell. Enzymes involved are P450 side-chain cleavage (P450scc), 3α-hydroxysteroid dehydrogenase (3α-HSD), 3β-hydroxysteroid dehydrogenase (3β-HSD) and 5α-reductase. Transport of cholesterol across the mitochondrial membrane is enhanced by the steroidogenic acute-regulatory (StAR) protein and the mitochondrial benzodiazepine receptor (MBR). 5α-DHP represents 5α-dihydroprogesterone.

Figure 2

Figure 2

Features of general structure of the neurosteroid. Figure shows intact four ring system that often contains hydroxyl side chains as sterols. Hydroxyl groups are denoted α if they are oriented above the plane (solid line), and α if they are oriented below the plane (dashed line). Stereoisomerism and structural modifications were discussed at carbon 3, 5, 6, 7, 17, 20, and 21 positions.

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References

    1. Adkins C. E., Pillai G. V., Kerby J., Bonnert T. P., Haldon C., McKernan R. M., Gonzalez J. E., Oades K., Whiting P. J., Simpson P. B. (2001). alpha4beta3delta GABA(A) receptors characterized by fluorescence resonance energy transfer-derived measurements of membrane potential. J. Biol. Chem. 276, 38934–3893910.1074/jbc.M104318200 - DOI - PubMed
    1. Akk G., Bracamontes J., Steinbach J. H. (2001). Pregnenolone sulfate block of GABA(A) receptors: mechanism and involvement of a residue in the M2 region of the alpha subunit. J. Physiol. (Lond.) 532, 673–68410.1111/j.1469-7793.2001.0673e.x - DOI - PMC - PubMed
    1. Akk G., Li P., Bracamontes J., Reichert D. E., Covey D. F., Steinbach J. H. (2008). Mutations of the GABA-A receptor alpha1 subunit M1 domain reveal unexpected complexity for modulation by neuroactive steroids. Mol. Pharmacol. 74, 614–62710.1124/mol.108.048520 - DOI - PMC - PubMed
    1. Akk G., Shu H. J., Wang C., Steinbach J. H., Zorumski C. F., Covey D. F., Mennerick S. (2005). Neurosteroid access to the GABAA receptor. J. Neurosci. 25, 11605–1161310.1523/JNEUROSCI.4173-05.2005 - DOI - PMC - PubMed
    1. Amin J., Weiss D. S. (1994). Homomeric rho 1 GABA channels: activation properties and domains. Recept. Channels 2, 227–236 - PubMed

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