Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., Honolulu, HI 96813, USA.
University of Hawaii Cancer Center, 651 Ilalo St., Honolulu, HI 96813, USA.
Function (Oxf). 2023 Dec 7;5(1):zqad069. doi: 10.1093/function/zqad069. eCollection 2024.
Cannabinoids are a major class of compounds produced by the plant Cannabis sativa. Previous work has demonstrated that the main cannabinoids cannabidiol (CBD) and tetrahydrocannabinol (THC) can have some beneficial effects on pain, inflammation, epilepsy, and chemotherapy-induced nausea and vomiting. While CBD and THC represent the two major plant cannabinoids, some hemp varieties with enzymatic deficiencies produce mainly cannabigerolic acid (CBGA). We recently reported that CBGA has a potent inhibitory effect on both Store-Operated Calcium Entry (SOCE) via inhibition of Calcium Release-Activated Calcium (CRAC) channels as well as currents carried by 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 the present study, we investigate the most common major and minor cannabinoids to determine their potential efficacy on TRPM7 channel function. We find that approximately half of the tested cannabinoids suppress 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 Mg and reduced by increases in intracellular Ca. Finally, we demonstrate that CBGA inhibits native TRPM7 channels in a B lymphocyte cell line. In conclusion, we demonstrate that CBGA is the most potent cannabinoid in suppressing TRPM7 activity and possesses therapeutic potential for diseases in which TRPM7 is known to play an important role such as cancer, stroke, and kidney disease.
大麻素是大麻植物产生的主要化合物类群。之前的工作表明，主要大麻素大麻二酚 (CBD) 和四氢大麻酚 (THC) 可能对疼痛、炎症、癫痫和化疗引起的恶心和呕吐有一些有益的作用。虽然 CBD 和 THC 代表了两种主要的植物大麻素，但一些酶缺乏的大麻品种主要产生大麻素酸 (CBGA)。我们最近报道 CBGA 通过抑制钙释放激活钙 (CRAC) 通道以及由通道激酶 TRPM7 携带的电流，对 Store-Operated Calcium Entry (SOCE) 具有很强的抑制作用。重要的是，CBGA 通过抑制这些机制在急性肾病小鼠模型中预防了肾脏损伤并抑制了炎症细胞因子的 mRNA 表达。在本研究中，我们研究了最常见的主要和次要大麻素，以确定它们对 TRPM7 通道功能的潜在功效。我们发现，大约一半的测试大麻素在某种程度上抑制了 TRPM7 电流，而 CBGA 对 TRPM7 的抑制作用最强。我们确定 CBGA 介导的 TRPM7 抑制需要一个功能激酶结构域，受细胞内 Mg⋅ATP 和游离 Mg 的敏化，并被细胞内 Ca 的增加所减少。最后，我们证明 CBGA 抑制了 B 淋巴细胞系中的天然 TRPM7 通道。总之，我们证明 CBGA 是抑制 TRPM7 活性的最有效大麻素，并且在 TRPM7 已知发挥重要作用的疾病（如癌症、中风和肾脏疾病）中具有治疗潜力。
