Receptor and Nonreceptor Membrane-Mediated Effects of THC and Cannabinoids

Abstract

A strict chemical nomenclature is first proposed. It is based on the definitions of cannabinoids, psychoactive (THC) and nonpsychoactive (CBD, CBN, and THC-11 oic acid), and of identified receptors (AEA and G protein) and their physiological ligands (arachidonyl ethanolamine [AEA] and arachidonyl diglycerol [2-AG]). THC is the only natural cannabinoid that interacts with a receptor protein in a stereospecific fashion, a property which is associated with its psychoactivity. Other natural, nonpsychoactive cannabinoids, CBN and CBD, vary over a wide range of concentration in marihuana preparations and antagonize the effects of THC. They also possess biological properties, activating membrane enzymes (phosphorylase and acyltransferase) that increase arachidonic acid biosynthesis.When THC binds a specific G-protein receptor, a structural change is induced that modifies an effector mechanism (e.g., decreased adenylate cyclase activity). THC does not interact directly with neurotransmitters or neuromodulators, but alters their response in a dose-related fashion (e.g., enhancing the response of a catechol receptor and decreasing the response of an acetylcholine receptor or modulating the response of opioid [mu and delta] receptors). Also, THC permeates the lipid bilayer and influences the integral membrane proteins through alteration of the boundary lipid. This effect is distinct from the mechanism resulting from AEA-G protein binding.It is proposed that AEA receptor interaction possesses a physiological function, which is to regulate the signaling between boundary lipids and the receptors or enzymes of the membrane in response to physiological stimuli. The boundary lipids surrounding the membrane proteins are the vehicles for the signals between the AEA receptor and the neurotransmitter receptors and their binding sites. The change of configuration of the AEA receptor modulates the signaling effect of the membrane on its enzymes and receptors. AEA, a by product of the membrane phospholipids, is an indirect signal modulator of membrane activity. THC can deregulate the physiological signling role of the G protein and its boundary lipid bilayer, a fundamental feature of all living cells. This deregulation of membrane signaling by THC results in partial and discordant effects.