Modulation of alpha7 nicotinic acetylcholine receptor by cannabidiol

Abstract

Cannabidiol (CBD), an important terpenoid compound from marijuana with no psychoactive effects, has become of great pharmaceutical interest for several health conditions. As CBD is a multitarget drug, there is a need to establish the molecular mechanisms by which CBD may exert therapeutic as well as adverse effects. The α7 nicotinic acetylcholine receptor is a cation-permeable ACh-gated channel present in the nervous system and in non-neuronal cells. It is involved in different pathological conditions, including neurological and neurodegenerative disorders, inflammation, and cancer. The aim of this work is to study α7 as one of the therapeutic targets of CBD in order to determine the mechanism by which the phytocannabinoid exerts its effect on the receptor. Wild-type and mutant α7 receptors were expressed in mammalian cells. To evaluate receptor ionotropic function, high-resolution single channel recordings in cell-attached and inside-out patch configurations were used. Changes in intracellular calcium levels were measured by confocal microscopy. We here reveal that CBD modulates α7 ionotropic and metabotropic functions. CBD leads to a concentration-dependent decrease of α7 single-channel activity with an IC50 of 0.54 ± 0.13 µM. The inhibition of α7 activity, which takes place through a membrane pathway, is neither mediated by receptor phosphorylation nor overcome by positive allosteric modulators and is compatible with CBD stabilization of resting or desensitized α7 conformational states. At the cellular level, CBD inhibits the increase in intracellular calcium triggered by α7 activation, thus decreasing cell calcium responses. The modulation of α7 is of pharmacological relevance and should be considered in the evaluation of CBD potential therapeutic uses. Thus, our study provides novel molecular information of CBD multiple actions and targets, which is required to set the basis for prospective applications in human health.