Transient receptor potential canonical 3 (TRPC3) protein belongs to the TRP family of nonselective cation channels. Its activation occurs by signaling through a G protein‐coupled receptor (GPCR) and a phospholipase C‐dependent (PLC) pathway. Perturbations in the expression of TRPC3 are associated with a plethora of pathophysiological conditions responsible for disorders of the cardiovascular, immune, and central nervous systems. The recently solved cryo‐EM structure of TRPC3 provides detailed inputs about the underlying mechanistic aspects of the channel, which in turn enables more efficient ways of designing small‐molecule modulators. Pharmacologically targeting TRPC3 in animal models has demonstrated great efficacy in treating diseases including cancers, neurological disorders, and cardiovascular diseases. Despite extensive scientific evidence supporting some strong correlations between the expression and activity of TRPC3 and various pathophysiological conditions, therapeutic strategies based on its pharmacological modulations have not led to clinical trials. The development of small‐molecule TRPC3 modulators with high safety, sufficient brain penetration, and acceptable drug‐like profiles remains in progress. Determining the pathological mechanisms for TRPC3 involvement in human diseases and understanding the requirements for a drug‐like TRPC3 modulator will be valuable in advancing small‐molecule therapeutics to future clinical trials. In this review, we provide an overview of the origin and activation mechanism of TRPC3 channels, diseases associated with irregularities in their expression, and new development in small‐molecule modulators as potential therapeutic interventions for treating TRPC3 channelopathies.

中文翻译：

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瞬时受体电位规范 3 离子通道的病理生理意义和调节

瞬时受体电位规范 3 (TRPC3) 蛋白属于非选择性阳离子通道的 TRP 家族。它的激活是通过 G 蛋白偶联受体 (GPCR) 和磷脂酶 C 依赖性 (PLC) 途径发出信号来实现的。 TRPC3 表达的扰动与多种导致心血管、免疫和中枢神经系统疾病的病理生理状况有关。最近解决的 TRPC3 冷冻电镜结构提供了有关通道基本机制方面的详细输入，这反过来又使设计小分子调制器的更有效方法成为可能。在动物模型中以药理学为靶点的 TRPC3 已被证明在治疗癌症、神经系统疾病和心血管疾病等疾病方面具有巨大功效。尽管大量科学证据支持 TRPC3 的表达和活性与各种病理生理状况之间存在很强的相关性，但基于其药理学调节的治疗策略尚未进入临床试验。具有高安全性、足够的脑渗透性和可接受的类药特征的小分子 TRPC3 调节剂的开发仍在进行中。确定 TRPC3 参与人类疾病的病理机制并了解类药物 TRPC3 调节剂的需求对于将小分子疗法推进到未来的临床试验具有重要意义。在这篇综述中，我们概述了 TRPC3 通道的起源和激活机制、与其表达不规则相关的疾病，以及小分子调节剂作为治疗 TRPC3 通道病的潜在治疗干预措施的新进展。