title: The sticky issue of neurosteroids and GABA(A) receptors.
abstract: Endogenous neurosteroids and their synthetic analogs (neuroactive steroids) are potent modulators of GABA(A) receptors. Thus, they are of physiological and clinical relevance for their ability to modulate inhibitory function in the CNS. Despite their importance, fundamental issues of neurosteroid actions remain unresolved. Recent evidence suggests that glutamatergic principal neurons, rather than glia, are the major sources of neurosteroid synthesis. Other recent studies have identified putative neurosteroid binding sites on GABA(A) receptors. In this Opinion, we argue that neurosteroids require a membranous route of access to transmembrane-domain binding sites within GABA(A) receptors. This has implications for the design of future neuroactive steroids because the lipid solubility and related accessibility properties of the ligand are likely to be key determinants of receptor modulation.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, USA.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Chisari
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Eisenman
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
authors.forename: Charles F
authors.initials: CF
authors.lastname: Zorumski
mesh_terms: D000818:Animals; D001665:Binding Sites; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D002490:Central Nervous System / Q000166:cytology / Q000502:physiology; D008958:Models, Molecular; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D011487:Protein Conformation; D011963:Receptors, GABA-A / Q000737:chemistry / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D011963:Receptors, GABA-A
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