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

Sigel, Erwin; Baur, Roland; Rácz, Ildiko; Marazzi, Janine; Smart, Trevor G; Zimmer, Andreas; Gertsch, Jürg (2011). The major central endocannabinoid directly acts at GABA(A) receptors. Proceedings of the National Academy of Sciences of the United States of America - PNAS, 108(44), pp. 18150-5. Washington, D.C.: National Academy of Sciences NAS 10.1073/pnas.1113444108

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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.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
UniBE Contributor:	Sigel, Erwin, Baur, Roland, Marazzi, Janine, Gertsch, Jürg
ISSN:	0027-8424
Publisher:	National Academy of Sciences NAS
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:23
Last Modified:	05 Dec 2022 14:06
Publisher DOI:	10.1073/pnas.1113444108
PubMed ID:	22025726
Web of Science ID:	000296373400057
URI:	https://boris.unibe.ch/id/eprint/8151 (FactScience: 213639)