Enteric Neuroscience Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
Therap Adv Gastroenterol. 2012 Jan;5(1):5-21. doi: 10.1177/1756283X11415892.
Gastrointestinal (GI) functional and motility disorders are highly prevalent and responsible for long-term morbidity and sometimes mortality in the affected patients. It is estimated that one in three persons has a GI functional or motility disorder. However, diagnosis and treatment of these widespread conditions remains challenging. This partly stems from the multisystem pathophysiology, including processing abnormalities in the central and peripheral (enteric) nervous systems and motor dysfunction in the GI wall. Interstitial cells of Cajal (ICCs) are central to the generation and propagation of the cyclical electrical activity and smooth muscle cells (SMCs) are responsible for electromechanical coupling. In these and other excitable cells voltage-sensitive ion channels (VSICs) are the main molecular units that generate and regulate electrical activity. Thus, VSICs are potential targets for intervention in GI motility disorders. Research in this area has flourished with advances in the experimental methods in molecular and structural biology and electrophysiology. However, our understanding of the molecular mechanisms responsible for the complex and variable electrical behavior of ICCs and SMCs remains incomplete. In this review, we focus on the slow waves and action potentials in ICCs and SMCs. We describe the constituent VSICs, which include voltage-gated sodium (Na(V)), calcium (Ca(V)), potassium (K(V), K(Ca)), chloride (Cl(-)) and nonselective ion channels (transient receptor potentials [TRPs]). VSICs have significant structural homology and common functional mechanisms. We outline the approaches and limitations and provide examples of targeting VSICs at the pores, voltage sensors and alternatively spliced sites. Rational drug design can come from an integrated view of the structure and mechanisms of gating and activation by voltage or mechanical stress.
胃肠道（GI）功能和运动障碍非常普遍，会导致受影响患者长期发病，有时甚至导致死亡。据估计，每三人中就有一人患有 GI 功能或运动障碍。然而，这些广泛存在的疾病的诊断和治疗仍然具有挑战性。这部分源于多系统病理生理学，包括中枢和外周（肠）神经系统处理异常以及 GI 壁的运动功能障碍。Cajal 间质细胞（ICC）是周期性电活动产生和传播的核心，平滑肌细胞（SMC）负责机电耦联。在这些和其他可兴奋细胞中，电压敏感离子通道（VSIC）是产生和调节电活动的主要分子单元。因此，VSIC 是干预 GI 运动障碍的潜在靶点。随着分子和结构生物学以及电生理学实验方法的进步，该领域的研究蓬勃发展。然而，我们对 ICC 和 SMC 复杂且可变的电行为负责的分子机制的理解仍然不完整。在这篇综述中，我们重点关注 ICC 和 SMC 中的慢波和动作电位。我们描述了组成性 VSIC，包括电压门控钠（Na(V)）、钙（Ca(V)）、钾（K(V)、K(Ca)）、氯（Cl(-)）和非选择性离子通道（瞬时受体电位 [TRPs]）。VSIC 具有显著的结构同源性和共同的功能机制。我们概述了方法和局限性，并提供了针对 VSIC 孔、电压传感器和选择性剪接位点的靶向示例。合理的药物设计可以来自对电压或机械应激门控和激活的结构和机制的综合观点。
