The major central endocannabinoid directly acts at GABA(A) receptors.

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 ?(2) confer 2-AG binding. 2-AG acts in a superadditive fashion with the neurosteroid 3?, 21-dihydroxy-5?-pregnan-20-one (THDOC) and modulates ?-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 ?(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.

SUBMITTER: Sigel E 

PROVIDER: S-EPMC3207709 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature