TY - JOUR
T1 - The sticky issue of neurosteroids and GABAA receptors
AU - Chisari, Mariangela
AU - Eisenman, Lawrence N.
AU - Covey, Douglas F.
AU - Mennerick, Steven
AU - Zorumski, Charles F.
N1 - Funding Information:
We thank lab members for support and Drs. Joe Henry Steinbach, Alex Evers, Gustav Akk, and Dave Reichert for discussion and their contributions to the work described here. We would like to dedicate this article to the memories of Drs. Erminio Costa and Alastair Hosie, both of whom made pivotal contributions to the field. This work was supported by the National Institute of General Medical Sciences (NIGMS), the National Institute of Mental Health (NIMH), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Neurological Disorders and Stroke (NINDS), and the Bantly Foundation.
PY - 2010/7
Y1 - 2010/7
N2 - Endogenous neurosteroids and their synthetic analogs (neuroactive steroids) are potent modulators of GABAA 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 GABAA receptors. In this Opinion, we argue that neurosteroids require a membranous route of access to transmembrane-domain binding sites within GABAA 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.
AB - Endogenous neurosteroids and their synthetic analogs (neuroactive steroids) are potent modulators of GABAA 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 GABAA receptors. In this Opinion, we argue that neurosteroids require a membranous route of access to transmembrane-domain binding sites within GABAA 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.
UR - http://www.scopus.com/inward/record.url?scp=77954382985&partnerID=8YFLogxK
U2 - 10.1016/j.tins.2010.03.005
DO - 10.1016/j.tins.2010.03.005
M3 - Article
C2 - 20409596
AN - SCOPUS:77954382985
VL - 33
SP - 299
EP - 306
JO - Trends in Neurosciences
JF - Trends in Neurosciences
SN - 0166-2236
IS - 7
ER -