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Three distinct CaM genes (CALM1, CALM2, and CALM3) encode one identical CaM protein in mammals. This low tolerance for structural changes highlights that CaM mutations are likely not well tolerated and therefore cause disease in humans. The first calmodulinopathies reported were catecholaminergic polymorphic ventricular tachycardia (CPVT) and a severe, early-onset cardiac arrhythmia syndrome with long-QT syndrome (LQTS). This led to recognition that CaM-modulated cardiac Cav1.2 L-type Ca2+ channels and RYR2 ryanodine receptors are key targets mediating the severe cardiac phenotype of CaM mutants . In this issue of the JGP, Hussey et al. (https:\/\/doi.org\/10.1085\/jgp.202413734) addressed the important question of whether dysregulation of voltage-gated Ca2+ channels in the brain could contribute to neurological\/neurodevelopmental symptoms that are also associated with calmodulinopathies.<\/jats:p>","DOI":"10.1085\/jgp.202613981","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T06:20:37Z","timestamp":1775542837000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Brain voltage-gated Ca2+ channels and calmodulin: Teaming up in calmodulinopathies?"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9406-7120","authenticated-orcid":true,"given":"J\u00f6rg","family":"Striessnig","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/054pv6659","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Pharmacy, University of Innsbruck 1 Department of Pharmacology and Toxicology, , Innsbruck,","place":["Austria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"2026051309460161300_bib1","doi-asserted-by":"publisher","DOI":"10.1113\/JP290671","article-title":"Drafting the calmodulation playbook: Emerging structural insights into transient receptor potential channel regulation by calmodulin","author":"Alemayhu","year":"2026","journal-title":"J. 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