{"title":"[Functional analysis of the mutant channels associated with skeletal muscle channelopathies].","authors":"Tomoya Kubota, Yuna Sakakibara","doi":"10.1254/fpj.25041","DOIUrl":"10.1254/fpj.25041","url":null,"abstract":"<p><p>Skeletal muscle channelopathies are rare genetic disorders caused by mutations in voltage-gated ion channel genes that regulate sarcomere excitability, including the CLCN1 gene encoding ClC-1, the KCNJ2 gene encoding Kir2.1, the SCN4A gene encoding Nav1.4, and the CACNA1S gene encoding Cav1.1. More than one hundred heterozygous missense mutations have been identified in SCN4A, representing a broad spectrum of clinical phenotypes, including sodium channel myotonia (SCM), paramyotonia congenita (PMC), hyperkalemic periodic paralysis (HyperPP) and hypokalemic periodic paralysis (HypoPP). In addition, recent case reports have shown that compound heterozygous mutations or homozygous mutations in SCN4A are associated with congenital myopathy or congenital myasthenic syndrome. Regarding the pathological mechanisms of SCM/PMC and HyperPP, a large number of electrophysiological analyses have shown an association between the functional alteration of the mutant Nav1.4 and the clinical phenotype. On the other hand, HypoPP has long been a mysterious disorder. In 2007, the recent discovery of aberrant leak currents, called \"gating pore currents\", brought a breakthrough in the field of HypoPP research and contributed to the elucidation of the structure-function relationship of the voltage sensing domain of voltage-gated ion channels. However, there has been little progress in the discovery of the therapeutics. Recently, we have generated HEK293T-based HypoPP model cell lines aiming to establish the in vitro platform for the high-throughput drug screening. Our HypoPP model cells would provide new insight into the development of novel therapeutics for channelopathies.</p>","PeriodicalId":12208,"journal":{"name":"Folia Pharmacologica Japonica","volume":"161 1","pages":"27-32"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145899279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"[MARCKS-mediated regulation of exocytotic amylase release: involvement of membrane domain dynamics].","authors":"Keitaro Satoh, Yuta Ohno, Haruna Nagase","doi":"10.1254/fpj.26020","DOIUrl":"https://doi.org/10.1254/fpj.26020","url":null,"abstract":"<p><p>Salivary secretion is essential for maintaining oral and systemic health. In parotid acinar cells, activation of the cAMP-protein kinase A (PKA) pathway following β-adrenergic receptor stimulation triggers the exocytosis of amylase. However, the downstream signaling pathways from PKA activation to exocytotic membrane fusion remain to be fully elucidated. In this review, we focused on Myristoylated alanine-rich C kinase substrate (MARCKS), a major protein kinase C (PKC) substrate, from the perspective of cell membrane homeostasis. Western blot analysis confirmed high MARCKS expression across various exocrine tissues, including the parotid, submandibular, sublingual, and lacrimal glands, as well as the exocrine pancreas. Our results revealed that β-adrenergic receptor stimulation activates PKCδ via PKA, leading to MARCKS phosphorylation in the parotid gland. Phosphorylated MARCKS dissociates from lipid rafts (detergent-resistant membranes) and translocates to the cytosol. Notably, stimulus-induced translocation from lipid rafts was observed in both cAMP-dependent (parotid) and Ca<sup>2+</sup>-dependent (pancreas) secretion. The inhibitory effect of a MARCKS-related peptide (MANS) on amylase secretion suggests that MARCKS functions as a physical or spatial regulator of secretion-related molecules, such as SNARE proteins, on lipid rafts. These findings indicate that MARCKS-mediated membrane domain regulation is a fundamental system underlying exocrine function. This review proposes a novel model of secretion regulated by MARCKS and discusses its pathophysiological significance as a potential therapeutic target for exocrine disorders.</p>","PeriodicalId":12208,"journal":{"name":"Folia Pharmacologica Japonica","volume":"161 4","pages":"245-248"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148367750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
