CALM2

CALM2 encodes calmodulin, a highly conserved calcium-binding sensor that mediates intracellular Ca²⁺ signal transduction and regulates numerous enzymes, ion channels, and cellular processes involved in proliferation and cell-cycle control^[1][2][3]. Mechanistically, calmodulin undergoes conformational changes upon Ca²⁺ binding and transduces calcium signals to downstream targets, thereby controlling diverse calcium-dependent signaling pathways across multiple tissues^[2][3][4]. In excitable cells, calmodulin is a critical regulator of voltage-gated calcium channels, including Ca_V1.2, where it contributes to calcium-dependent inactivation and maintenance of cellular calcium homeostasis^[4][5]. Disease-associated CALM2 variants disrupt these regulatory functions and are strongly linked to severe cardiac arrhythmia phenotypes, particularly congenital long QT syndrome and related calmodulinopathies^[1][5][6]. In human disease models, pathogenic calmodulin mutations impair calcium binding and alter ion-channel regulation, leading to abnormal electrophysiological activity and increased arrhythmic risk^[4][5][6]. Compared with related isoforms, CALM2, CALM1, and CALM3 encode an identical calmodulin protein but differ at the nucleotide and genomic levels, making gene-specific variant analysis essential for understanding disease mechanisms and genotype-phenotype relationships^[1][2][5]. For experimental applications, CALM2 serves as a valuable model for investigating calcium signaling, ion-channel regulation, and inherited arrhythmia mechanisms, while disease-associated variants provide tools for functional studies in cellular and induced pluripotent stem cell systems^[5][6].