The major central endocannabinoid directly acts at GABAAreceptors

• DOI: 10.1073/pnas.1113444108
• Publication Date: 2011-10-25T05:52:20Z
• Authors: Erwin Sigel; Roland Baur; Ildiko Rácz; Janine Marazzi; Trevor G. Smart; Andreas Zimmer; Jürg Gertsch
• Keywords: Mice, Knockout; 0301 basic medicine; Mice; 03 medical and health sciences; Cannabinoid Receptor Modulators; Animals; Amino Acids; Receptors, GABA-A; Locomotion; Endocannabinoids; 3. Good health

GABAAreceptors 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 GABAAreceptors at low concentrations of GABA. Two residues of the receptor located in the transmembrane segment M4 of β2confer 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 CB1/CB2cannabinoid receptor double-KO, whereas β2-KO mice show hypermotility. The identification of a functional binding site for 2-AG in the GABAAreceptor may have far-reaching consequences for the study of locomotion and sedation.