Psychoactive cannabinoids and membrane signaling

THC-like psychoactive cannabinoids permeate the lipid bilayer of the membra ne, altering its physicochemical properties and activating phospholipases. As a result, an increased production of arachidonic acid occurs with its ca scade of eicosanoids, including prostaglandins. In addition, THC and its ps ychoactive derivatives bind within the membrane in a stereospecific fashion , to a transmembrane G protein coupled receptor (GPCR) for which THC has a much higher affinity than the natural ligands, arachidonylethanolamide (AEA ) and 2-arachidonyglycerol (2-AG). These natural lipid ligands may be consi dered signaling molecules which are generated in the membrane lipid bilayer . THC alters the physicochemical disposition of the lipid bilayer and inter acts with the integral membrane protein receptors through alteration of the boundary lipid. This effect is distinct from the mechanism resulting from its persistent binding to a G protein coupled transmembrane receptor. THC d oes not interact directly with neurotransmitter receptors but alters their pharmacological response in an allosteric fashion. It is proposed that the binding of AEA. and 2-AG to the G protein coupled transmembrane receptor po ssesses a physiological function which is to regulate the signaling between boundary lipids and membrane receptors in response to extracellular signal s. AEA and 2-AG are eicosanoid signaling molecules which modulate the activ ity of G protein coupled transmembrane receptors. AEA and 2-AG should not b e identified with synthetic ligand molecules dubbed 'endogenous cannabinoid s' which are 'xenobiotics' with no physiological regulating function. THC d eregulates persistently a basic signaling mechanism of the membrane lipid b ilayer and of its integrated receptors with resulting impairment of cellula r function of brain, heart and male gonads. Copyright (C) 2000 John Wiley & Sons, Ltd.