Cannabigerolic Acid (CBGA) inhibits the TRPM7 ion channel through its kinase domain

Cannabinoids are a major class of compounds produced by the plant Cannabis sativa. The most studied of these phytocannabinoids are cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). Previous work has demonstrated some therapeutic effects of cannabinoids on pain, inflammation, epilepsy, and chemotherapy-induced nausea and vomiting. However, the precise mechanisms of action of these cannabinoids remain poorly understood. While in most cannabis plant varieties CBD and THC represent the two major cannabinoids, other varieties—referred to as hemp—lack the enzymatic activity to produce significant amounts of THC and mainly produce CBD. Some hemp varieties additionally lack the enzymatic activity to produce CBD, resulting in a plant in which the main molecular cannabinoid species is cannabigerolic acid (CBGA). We recently reported that CBGA has a potent inhibitory effect on both Store-Operated Calcium Entry (SOCE) via inhibition Calcium Release-Activated Calcium (CRAC) channels as well as the channel-kinase TRPM7. Importantly, CBGA prevented kidney damage and suppressed mRNA expression of inflammatory cytokines through inhibition of these mechanisms in an acute nephropathic mouse model. In this study, we comprehensively investigated the most common major and minor cannabinoids to determine their potential efficacy on TRPM7 channel function. Here, we found that approximately half of the cannabinoids tested suppressed TRPM7 currents to some degree, with CBGA having the strongest inhibitory effect on TRPM7. We determined that the CBGA-mediated inhibition of TRPM7 requires a functional kinase domain, is sensitized by both intracellular Mg⋅ATP and free Mg2+, and reduced by increases in intracellular Ca2+. Finally, we demonstrate that CBGA inhibits native TRPM7 in B lymphocytes cell line. In conclusion, we demonstrate that CBGA is the most potent cannabinoid in suppressing TRPM7 activity and possesses the potential to be a pharmacologic therapeutic for diseases in which TRPM7 is known to play an important role such as cancer, stroke, and kidney disease.