Imbrici Paola, Liantonio Antonella, Camerino Giulia M, De Bellis Michela, Camerino Claudia, Mele Antonietta, Giustino Arcangela, Pierno Sabata, De Luca Annamaria, Tricarico Domenico, Desaphy Jean-Francois, Conte Diana
Department of Pharmacy - Drug Sciences, University of Bari "Aldo Moro" Bari, Italy.
Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro" Bari, Italy.
Front Pharmacol. 2016 May 10;7:121. doi: 10.3389/fphar.2016.00121. eCollection 2016.
In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets.
在人类基因组中，400多个基因编码离子通道，离子通道是介导离子跨膜流动的跨膜蛋白。它们在所有细胞类型中均有表达，几乎参与了所有生理过程，包括感官知觉、神经传递、肌肉收缩、分泌、免疫反应、细胞增殖和分化。由于离子通道广泛的组织分布及其生理功能，编码离子通道亚基或其相互作用蛋白的基因突变会导致遗传性离子通道病。这些疾病涵盖从常见到极为罕见的病症，其严重程度可轻可重，有的会导致残疾，甚至危及生命。尽管如此，离子通道只是约5%的已上市药物的主要靶点，这表明它们在药物研发方面具有潜力。本综述总结了由钙、钠、钾和氯离子通道突变引起的中枢和外周神经系统、心脏、肾脏、骨骼、骨骼肌和胰腺主要离子通道病的治疗方法。对于大多数通道病，治疗主要是经验性和对症性的，常常因对大量患者缺乏疗效和耐受性而受到限制。其他通道病可使用针对离子通道的药物，如已上市的钠通道阻滞剂。因此，需要开发新的、更具特异性的治疗方法。为此，通道病药物治疗的一项重大进展是发现离子通道突变会导致生物物理学变化，进而可特异性改变对药物的敏感性：这为药物遗传学策略开辟了道路，使个性化治疗的开发成为可能，提高疗效并减少副作用。此外，在离子通道病中识别疾病修饰因子似乎是发现新的可成药靶点的另一种策略。
