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

Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18150-5. doi: 10.1073/pnas.1113444108. Epub 2011 Oct 24.

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Cannabinoid Receptor Modulators / physiology*
  • Endocannabinoids*
  • Locomotion
  • Mice
  • Mice, Knockout
  • Receptors, GABA-A / chemistry
  • Receptors, GABA-A / physiology*

Substances

  • Amino Acids
  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Receptors, GABA-A