CaV1.2 channelopathic mutations evoke diverse pathophysiological mechanisms

• DOI: 10.1085/jgp.202213209
• Publication Date: 2022-09-27T21:15:10Z
• Authors: Moradeke A. Bamgboye; Kevin G. Herold; Daiana C.O. Vieira; Maria K. Traficante; Philippa J. Rogers; Manu Ben-Johny; Ivy E. Dick
• Keywords: Pathogenesis; Neurodevelopmental disorder; Pathophysiology

The first pathogenic mutation in CaV1.2 was identified 2004 and shown to cause a severe multisystem disorder known as Timothy syndrome (TS). localized the distal S6 region of channel, play major role channel activation. TS patients suffer from life-threatening cardiac symptoms well significant neurodevelopmental deficits, including autism spectrum (ASD). Since this discovery, number variety mutations have grown tremendously, regions remain frequent locus for many these mutations. While majority harboring exhibit that can be explained by mechanisms, same cannot said ASD or phenotypes seen some patients, indicating gap our understanding pathogenesis channelopathies. Here, we use whole-cell patch clamp, quantitative Ca2+ imaging, single recordings expand mechanisms underlying Specifically, find within exert independent separable effects on activation, voltage-dependent inactivation (VDI), Ca2+-dependent (CDI). Moreover, CDI are varied include altered opening possible disruption transduction. Overall, results provide structure–function framework conceptualize pathophysiology offer insight into biophysical defects associated with distinct clinical manifestations.