Effects of cannabinoids on ligand-gated ion channels

Abstract

Phytocannabinoids such as Δ⁹-tetrahydrocannabinol and cannabidiol, endocannabinoids such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and synthetic cannabinoids such as CP47,497 and JWH-018 constitute major groups of structurally diverse cannabinoids. Along with these cannabinoids, CB1 and CB2 cannabinoid receptors and enzymes involved in synthesis and degradation of endocannabinoids comprise the major components of the cannabinoid system. Although, cannabinoid receptors are known to be involved in anti-convulsant, anti-nociceptive, anti-psychotic, anti-emetic, and anti-oxidant effects of cannabinoids, in recent years, an increasing number of studies suggest that, at pharmacologically relevant concentrations, these compounds interact with several molecular targets including G-protein coupled receptors, ion channels, and enzymes in a cannabinoid-receptor independent manner. In this report, the direct actions of endo-, phyto-, and synthetic cannabinoids on the functional properties of ligand-gated ion channels and the plausible mechanisms mediating these effects were reviewed and discussed.

Keywords: cannabinoids; endocannabinoids; ion channels; ligand-gated ion channels; synthetic cannabinoids.

FIGURE 1

Cannabinoids interact with the lipid membrane and influence the functional properties of ion channels and other integral membrane proteins. Cannabinoids enter the lipid membrane and binds to cannabinoid receptors through lipid membrane (Reggio and Traore, 2000; Barnett-Norris et al., 2005; Makriyannis et al., 2005). In addition, cannabinoids directly affect channel function by changing the biophysical properties of the lipid membrane or binding to a hydrophobic binding site(s) located on the transmembrane regions of ligand-gated ion channels (represented with large dashed red arrow). Cannabinoids, like other lipophilic molecules, partition into the lipid bilayer and alter the biophysical properties of the membrane by reducing membrane electrical resistance, increasing membrane fluidity, changing membrane order, increasing membrane stiffness, increasing membrane elasticity, and changing physicochemical and structural properties of bilayer membranes (represented with thinner diagonal red arrows). Secondly, cannabinoids can bind directly to transmembrane domains of ion channels embedded in the cell membrane (see discussion).