Conservation of Ca~(2+)/Calmodulin Regulation across Na and Ca~(2+) Channels

摘要

Voltage-gated Na and Ca~(2+) 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 Ca~(2+)channels, carboxyl-tail interactions with calmodulin do elaborate robust and similar forms of Ca~(2+) regulation. However, Na channels have only shown subtler Ca~(2+) modulation that differs among reports, challenging attempts at unified understanding. Here, by rapid Ca~(2+) photorelease onto Na channels, we reset this view of Na channel regulation. For cardiacmuscle channels (Na_V1.5), reported effects from which most mechanistic proposals derive, we observe no Ca~(2+) modulation. Conversely, for skeletalmuscle channels (Na_V1.4), we uncover fast Ca~(2+) regulation eerily similar to that of Ca~(2+) channels. Channelopathic myotonia mutations halve NaV1.4 Ca~(2+) regulation, and transplanting the NaV1.4 carboxy tail onto Ca~(2+) channels recapitulates Ca~(2+) regulation. Thus, we argue for the persistence and physiological relevance of an ancient Ca~(2+) regulatory module across Na and Ca~(2+) channels.