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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-11, Vol.108 (44), p.18150-18155
• Main Authors: Sigel, Erwin, Baur, Roland, Rácz, Ildiko, Marazzi, Janine, Smart, Trevor G, Zimmer, Andreas, Gertsch, Jürg
• Format: Article
• Language: English
• Subjects: Amino Acids - chemistry; Animals; Cannabinoid Receptor Modulators - physiology; Endocannabinoids; Locomotion; Mice; Mice, Knockout; Receptors, GABA-A - chemistry; Receptors, GABA-A - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1113444108

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.