Tricarico Domenico, Camerino Diana Conte
Department of Pharmacobiology, Faculty of Pharmacy, University of Bari Italy.
Front Pharmacol. 2011 Feb 28;2:8. doi: 10.3389/fphar.2011.00008. eCollection 2011.
The periodic paralysis (PP) are rare autosomal-dominant disorders associated to mutations in the skeletal muscle sodium, calcium, and potassium channel genes characterized by muscle fiber depolarization with un-excitability, episodes of weakness with variations in serum potassium concentrations. Recent advances in thyrotoxic PP and hypokalemic PP (hypoPP) confirm the involvement of the muscle potassium channels in the pathogenesis of the diseases and their role as target of action for drugs of therapeutic interest. The novelty in the gating pore currents theory help to explain the disease symptoms, and open the possibility to more specifically target the disease. It is now known that the fiber depolarization in the hypoPP is due to an unbalance between the novel identified depolarizing gating pore currents (I(gp)) carried by protons or Na(+) ions flowing through aberrant alternative pathways of the mutant subunits and repolarizing inwardly rectifying potassium channel (Kir) currents which also includes the ATP-sensitive subtype. Abnormal activation of the I(gp) or deficiency in the Kir channels predispose to fiber depolarization. One pharmacological strategy is based on blocking the I(gp) without affecting normal channel gating. It remains safe and effective the proposal of targeting the K(ATP), Kir channels, or BK channels by drugs capable to specifically open at nanomolar concentrations the skeletal muscle subtypes with less side effects.
周期性瘫痪（PP）是罕见的常染色体显性疾病，与骨骼肌钠、钙和钾通道基因突变相关，其特征为肌纤维去极化且无兴奋性，伴有血清钾浓度变化的肌无力发作。甲状腺毒症性PP和低钾性PP（低钾性周期性麻痹，hypoPP）的最新进展证实了肌肉钾通道在疾病发病机制中的作用及其作为治疗相关药物作用靶点的角色。门控孔电流理论的新进展有助于解释疾病症状，并为更特异性地针对该疾病提供了可能性。现在已知低钾性周期性麻痹中的肌纤维去极化是由于质子或钠离子通过突变亚基的异常替代途径携带的新发现的去极化门控孔电流（I(gp)）与使膜复极化的内向整流钾通道（Kir）电流（其中还包括ATP敏感性亚型）之间失衡所致。I(gp)的异常激活或Kir通道的缺陷易导致肌纤维去极化。一种药理学策略是基于阻断I(gp)而不影响正常通道门控。通过能够以纳摩尔浓度特异性开放骨骼肌亚型且副作用较小的药物靶向K(ATP)、Kir通道或BK通道的提议仍然是安全有效的。
