Functional sites involved in modulation of the GABA(A) receptor channel by the intravenous anesthetics propofol, etomidate and pentobarbital

摘要

GABA(A) receptors are the major inhibitory neurotransmitter receptors in the brain and are the target for many clinically important drugs. Among the many modulatory compounds are also the intravenous anesthetics propofol and etomidate, and barbiturates. The mechanism of receptor modulation by these compounds is of mayor relevance. The site of action of these compounds has been located to subunit interfaces in the intra-membrane region of the receptor. In alpha(1)beta(2)gamma(2) GABA(A) receptors there are five such interfaces, two beta+/alpha- and one each of alpha+/gamma-, and gamma+/beta- subunit interfaces. We have used reporter mutations located in the second trans-membrane region in different subunits to probe the effects of changes at these subunit interfaces on modulation by propofol, etomidate and pentobarbital. We provide evidence for the fact that each of these compounds either modulates through a different set of subunit interfaces or through the same set of subunit interfaces to a different degree. As a GABA(A) receptor pentamer harbors two beta+/alpha- subunit interfaces, we used concatenated receptors to dissect the contribution of individual interfaces and show that only one of these interfaces is important for receptor modulation by etomidate. (C) 2016 Elsevier Ltd. All rights reserved.