The major central endocannabinoid directly acts at GABA(A) receptors.
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.
Institute of Biochemistry and Molecular Medicine, University of Bern, CH-3012 Bern, Switzerland. sigel@ibmm.unibe.ch
Erwin
E
Sigel
Roland
R
Baur
Ildiko
I
Rácz
Janine
J
Marazzi
Trevor G
TG
Smart
Andreas
A
Zimmer
Jürg
J
Gertsch
D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D063388:Endocannabinoids; D008124:Locomotion; D051379:Mice; D018345:Mice, Knockout; D011963:Receptors, GABA-A / Q000737:chemistry / Q000502:physiology*
D000596:Amino Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D011963:Receptors, GABA-A