Folia Pharmacologica Japonica最新文献

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.

Skeletal muscle is composed of thousands of myofibers that enable contraction and relaxation. Myofibers are constantly exposed to biophysical stresses during repeated contractile processes; nevertheless, skeletal muscle maintains its "resilience" through both structural robustness and the ability to sense and adapt to biophysical forces. Regulation of intra- and extracellular ionic concentrations is a critical determinant for cell growth, fate determination, and death. In myofibers, Ca²⁺ release from sarcoplasmic reticulum is well established as the trigger for myofiber contraction, whereas accumulating evidence suggests the importance of Ca²⁺ influx across sarcolemma in myofiber homeostasis. Moreover, other ions such as magnesium ion are increasingly recognized for their roles in skeletal muscle functions. In this review, we summarize the current understandings of adaptive mechanisms dependent on Ca²⁺ influx in response to biophysical stresses, with a particular focus on membrane repair and myofiber regeneration processes.

Regulation of thermogenesis in mammals is essential for maintaining body temperature homeostasis under fluctuating environmental temperature. Impairments in this regulation can lead to severe conditions, including fever or heatstroke. This review focuses on malignant hyperthermia (MH), a pathological escalation of thermogenesis in skeletal muscle. It highlights the role of type 1 ryanodine receptor (RYR1), a Ca²⁺ release channel, based on our recent studies. Previous studies have revealed that genetic mutations in RYR1 are associated with muscle disorders including MH, which are characterized by abnormal Ca²⁺-induced Ca²⁺ release (CICR). To test our hypothesis that RYR1 channel function is closely related to thermogenesis, we examined cultured cell lines expressing wild-type or MH-related mutants of RYR1, as well as muscle cells prepared from MH model mice. Using a local heating microscopy combined with fluorescence temperature imaging, we identified a novel phenomenon termed heat-induced Ca²⁺ release (HICR). Furthermore, our results indicate that anesthesia induces simultaneous increases in temperature and cytoplasmic Ca²⁺ concentration in muscle cells. Based on these findings, we propose a positive feedback loop where HICR drives further Ca²⁺ release during MH episodes, causing thermogenesis and further elevation of body temperature. This review summarizes our experimental results that were presented at the symposium, providing greater detail on the mechanisms underlying MH pathogenesis and the role of RYR1 in thermal regulation.

Fluorescent biosensors have become essential tools in life sciences, enabling the visualization of the spatiotemporal dynamics of signaling molecules at the cellular level. In particular, intensity-based sensors-where changes in the concentrations of signaling molecules are detected as changes in fluorescence intensity-are widely used due to their versatility. However, such sensors are often affected by several factors, including variations in biosensor concentration, photobleaching, optical path settings, and focus drift, which hamper quantitative analysis. To overcome these challenges, we have been developing fluorescence lifetime imaging microscopy (FLIM)-based biosensors that utilize fluorescence lifetime-a parameter independent of probe concentration and imaging conditions-as a robust and reliable readout. Our research has focused on the quantitative visualization of physiological parameters, particularly those relevant to skeletal muscle homeostasis and ion channel activity. One example is a small-molecule fluorescent temperature sensor designed to quantify temperature changes in subcellular compartments. This sensor, based on an organic dye, enables targeting to organelle membranes and provides high spatial resolution, allowing precise detection of local heat production, such as that occurring in the mitochondria of brown adipocytes. In parallel, we have developed genetically encoded fluorescent protein-based sensors that correlate fluorescence lifetime values with the concentrations of signaling molecules such as ATP. These sensors have enabled the quantitative imaging of ATP dynamics in various cell types and multicellular systems. Furthermore, we are constructing a flexible sensor development platform, paving the way for the creation of diverse biosensors that can contribute to comprehensive studies in muscle physiology.

Ozanimod hydrochloride (Product name: ZEPOZIA^® Capsule Starter Pack, ZEPOZIA^® Capsules 0.92 mg; Nonproprietary name: ozanimod hydrochloride, hereinafter referred to as ozanimod) is an orally available receptor modulator that acts on the sphingosine 1-phosphate (S1P) receptor and selectively binds with high affinity to S1P₁ and S1P₅ receptors. Following binding to and activation of S1P₁ receptors, ozanimod acts as a functional S1P₁ receptor antagonist by inducing internalization of S1P₁ receptors expressed on the surface of cells such as lymphocytes through agonism of S1P₁ receptors. These effects may ameliorate the pathologic changes of the autoimmune disease ulcerative colitis (UC). The Japanese phase II/III study (Study RPC01-3103) demonstrated the efficacy and safety of this drug in Japanese patients with moderate to severe ulcerative colitis. In Japan, it was approved by the Ministry of Health, Labour and Welfare (MHLW) in December 2024 for the treatment of moderate to severe UC in patients who have had an inadequate response to conventional therapies, and was launched in March 2025. Existing UC treatments show significant therapeutic effects, but medications for moderate to severe UC have respective advantages and disadvantages in efficacy, safety, and administration routes. No treatment meets all criteria. Ozanimod, with a novel mechanism, offers sustained high efficacy in improving clinical symptoms and mucosal damage in moderate to severe UC patients. It has a favorable safety profile, high medication compliance, and is a convenient oral treatment for long-term use. Thus, providing Ozanimod as a new UC treatment option is of high clinical significance.