Yin Ying, Park Cheon-Gyu, Feng Shasha, Guan Ziqiang, Lee Hyuk-Joon, Zhang Feng, Sharma Kedar, Borgnia Mario J, Im Wonpil, Lee Seok-Yong
Department of Biochemistry, Duke University School of Medicine, Durham, NC, USA.
Department of Biological Sciences, Lehigh University, Bethlehem, PA, USA.
Nat Struct Mol Biol. 2025 May;32(5):828-840. doi: 10.1038/s41594-024-01463-8. Epub 2025 Jan 14.
Transient receptor potential channel subfamily M member 3 (TRPM3) is a Ca-permeable cation channel activated by the neurosteroid pregnenolone sulfate (PregS) or heat, serving as a nociceptor in the peripheral sensory system. Recent discoveries of autosomal dominant neurodevelopmental disorders caused by gain-of-function mutations in TRPM3 highlight its role in the central nervous system. Notably, the TRPM3 inhibitor primidone, an anticonvulsant, has proven effective in treating patients with TRPM3-linked neurological disorders and in mouse models of thermal nociception. However, our understanding of neurosteroids, inhibitors and disease mutations on TRPM3 is limited. Here we present cryogenic electron microscopy structures of the mouse TRPM3 in complex with cholesteryl hemisuccinate, primidone and PregS with the synthetic agonist CIM 0216. Our studies identify the binding sites for the neurosteroid, synthetic agonist and inhibitor and offer insights into their effects and disease mutations on TRPM3 gating, aiding future drug development.
瞬时受体电位通道M亚家族成员3（TRPM3）是一种钙通透性阳离子通道，可被神经甾体硫酸孕烯醇酮（PregS）或热激活，在外周感觉系统中作为伤害感受器。最近发现由TRPM3功能获得性突变引起的常染色体显性神经发育障碍，突出了其在中枢神经系统中的作用。值得注意的是，TRPM3抑制剂扑米酮（一种抗惊厥药）已被证明可有效治疗患有TRPM3相关神经疾病的患者以及热痛觉过敏小鼠模型。然而，我们对神经甾体、抑制剂和疾病突变对TRPM3的影响的了解有限。在这里，我们展示了与半琥珀酸胆固醇、扑米酮、PregS以及合成激动剂CIM 0216结合的小鼠TRPM3的低温电子显微镜结构。我们的研究确定了神经甾体、合成激动剂和抑制剂的结合位点，并深入了解了它们对TRPM3门控的影响以及疾病突变，有助于未来的药物开发。
