Conservation of Ca²⁺/calmodulin regulation across Na and Ca ²⁺ channels

Voltage-gated Na and Ca²⁺ channels comprise distinct ion channel superfamilies, yet the carboxy tails of these channels exhibit high homology, hinting at a long-shared and purposeful module. For different Ca²⁺ channels, carboxyl-tail interactions with calmodulin do elaborate robust and similar forms of Ca²⁺ regulation. However, Na channels have only shown subtler Ca²⁺ modulation that differs among reports, challenging attempts at unified understanding. Here, by rapid Ca²⁺ photorelease onto Na channels, we reset this view of Na channel regulation. For cardiac-muscle channels (Na_V1.5), reported effects from which most mechanistic proposals derive, we observe no Ca²⁺ modulation. Conversely, for skeletal-muscle channels (Na_V1.4), we uncover fast Ca²⁺ regulation eerily similar to that of Ca²⁺ channels. Channelopathic myotonia mutations halve Na_V1.4 Ca²⁺ regulation, and transplanting the Na_V1.4 carboxy tail onto Ca ²⁺ channels recapitulates Ca²⁺ regulation. Thus, we argue for the persistence and physiological relevance of an ancient Ca²⁺ regulatory module across Na and Ca²⁺ channels.