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In addition, many patients exhibit neurological comorbidities, including developmental delay and autism spectrum disorder. Prior studies have identified the impairment of Ca2+\/CaM-dependent inactivation (CDI) of CaV1.2 channels as a major pathogenic mechanism leading to the LQTS phenotype in these patients. However, the impact of these mutations on other voltage-gated calcium channels (VGCCs) has yet to be fully explored. Here, we examine the potential for pathological CaM variants to impair the Ca2+\/CaM-dependent regulation of CaV1.3 and CaV2.1, both essential for neuronal function. We find that pathogenic mutations in CaM can impair the CDI of CaV1.3, with overlapping yet distinct disruption of the Ca2+-dependent facilitation (CDF) of CaV2.1 channels. Moreover, while the majority of CaM variants demonstrated the ability to bind the IQ region of each channel, differences were noted between CaV1.3 and CaV2.1, demonstrating unique CaM interactions across the two channel subtypes. Further, C-lobe CaM variants display a reduced ability to sense Ca2+ when in complex with the CaV IQ domains, explaining the Ca2+\/CaM regulation deficits. Overall, these results support the possibility that disrupted Ca2+\/CaM regulation of multiple VGCCs may contribute to the pathogenesis of calmodulinopathies.<\/jats:p>","DOI":"10.1085\/jgp.202413734","type":"journal-article","created":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T07:20:38Z","timestamp":1772781638000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Calmodulinopathy variants impair CaV1.3 and CaV2.1 regulation"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1357-747X","authenticated-orcid":true,"given":"John W.","family":"Hussey","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/055yg0521","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Maryland School of Medicine 1 Department of Pharmacology and Physiology, , Baltimore, 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