Journal
TRENDS IN NEUROSCIENCES
Volume 33, Issue 7, Pages 299-306Publisher
ELSEVIER SCIENCE LONDON
DOI: 10.1016/j.tins.2010.03.005
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Funding
- National Institute of General Medical Sciences (NIGMS)
- National Institute of Mental Health (NIMH)
- National Institute on Alcohol Abuse and Alcoholism (NIAAA)
- National Institute of Neurological Disorders and Stroke (NINDS)
- Bantly Foundation
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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.
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