The Major Central Endocannabinoid Directly Acts at GABA(A) Receptors

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2011 Oct 26

PMID 22025726

Citations 75

Authors

Erwin Sigel

Roland Baur

Ildiko Racz

Janine Marazzi

Trevor G Smart

Andreas Zimmer

Jurg Gertsch

Affiliations

Soon will be listed here.

Abstract

GABA(A) receptors are the major ionotropic inhibitory neurotransmitter receptors. The endocannabinoid system is a lipid signaling network that modulates different brain functions. Here we show a direct molecular interaction between the two systems. The endocannabinoid 2-arachidonoyl glycerol (2-AG) potentiates GABA(A) receptors at low concentrations of GABA. Two residues of the receptor located in the transmembrane segment M4 of β(2) confer 2-AG binding. 2-AG acts in a superadditive fashion with the neurosteroid 3α, 21-dihydroxy-5α-pregnan-20-one (THDOC) and modulates δ-subunit-containing receptors, known to be located extrasynaptically and to respond to neurosteroids. 2-AG inhibits motility in CB(1)/CB(2) cannabinoid receptor double-KO, whereas β(2)-KO mice show hypermotility. The identification of a functional binding site for 2-AG in the GABA(A) receptor may have far-reaching consequences for the study of locomotion and sedation.

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