Abstract
Type-A GABA receptors are vitally important for brain function. They provide a dampening mechanism for neural excitation across the CNS. Inhibitory neurosteroids are naturally synthesised in the brain and released where they can modulate GABA-A receptors and thus brain physiology. Recent analysis suggests that these neurosteroids may bind within the receptor’s transmembrane domain, with an ion channel location also being proposed. To date the exact location, and there may be more than one, remain unknown. Here, we will use electrophysiology coupled with molecular and structural biology to locate these important sites thereby enabling their physiological relevance to be identified.
References
1. Laverty, D, Desai, R, Uchariski, T, Masiulis, S, Stec, WJ, Malinauskas, T, Zivanov, J, Pardon, E, Steyaert, J, Miller, KW & Aricescu, AR. (2019). Cryo-EM structure of the human a1b3g2 GABAA receptor in a lipid bilayer. Nature, 565, 516-522.
2. Laverty, D, Thomas, P, Field, M, Andersen, OJ, Gold, MG, Biggin, PC, Gielen, M & Smart, TG. (2017). Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites. Nature Structural & Molecular Biology, 24, 977-985.
3. Seljeset, S, Bright, DP, Thomas, P & Smart, TG. (2018). Probing GABAA receptors with inhibitory neurosteroids. Neuropharmacology, 136, 23-36.
4. Seljeset, S, Laverty, D & Smart, TG. (2015). Inhibitory neurosteroids and the GABAA receptor. Adv Pharmacol, 72, 165-187.
5. Twede, V, Tartaglia, AL, Covey, DF & Bamber, BA. (2007). The Neurosteroids Dehydroepiandrosterone Sulfate and Pregnenolone Sulfate Inhibit the UNC-49 GABA Receptor through a Common Set of Residues. Mol Pharmacol, 72, 1322-1329.