Towards a Unified Theory of Calmodulin Regulation (Calmodulation) of Voltage-Gated Calcium and Sodium Channels

Abstract

Voltage-gated Na and Ca2+ channels represent two major ion channel families that enable myriad biological functions including the generation of action potentials and the coupling of electrical and chemical signaling in cells. Calmodulin regulation (calmodulation) of these ion channels comprises a vital feedback mechanism with distinct physiological implications. Though long-sought, a shared understanding of the channel families remained elusive for two decades as the functional manifestations and the structural underpinnings of this modulation often appeared to diverge. Here, we review recent advancements in the understanding of calmodulation of Ca2+ and Na channels that suggest a remarkable similarity in their regulatory scheme. This interrelation between the two channel families now paves the way towards a unified mechanistic framework to understand vital calmodulin-dependent feedback and offers shared principles to approach related channelopathic diseases. An exciting era of synergistic study now looms.

Calcium triggers reversal of calmodulin on nested anti-parallel sites in the IQ motif of the neuronal voltage-dependent sodium channel Na V 1.2

“…[15, 16, 22, 33, 41] These studies of Na V -CaM interactions contrast with the behavior of IQ motifs in voltage-dependent calcium channels such as Ca V 1.2, which interacts with both domains of CaM and has a higher affinity for (Ca 2+ ) 4 -CaM than apo CaM [89–91], despite the similarities between the calcium and sodium channels. [92]…”

“…[92, 116–119] For many of these channels, CaM is associated under resting (low calcium) conditions as it is with Na V 1.2. CaM may activate, inhibit, or do both, depending on its fractional saturation by calcium.…”

Calcium transport across plant membranes: mechanisms and functions

“…Calcium entry through CNGCs evolved self‐inactivation machinery to prevent Ca 2+ overload and shape calcium signals. The classical Ca 2+ ‐dependent inactivation (CDI) of animal CNGCs, which includes interaction between CNGC‐embedded calmodulin (CaM) and Ca 2+ (Ben‐Johny et al ., ), was suggested to operate in higher plants (Köhler et al ., ; Köhler & Neuhaus, ). Binding CaM in the presence of elevated [Ca 2+ ] cyt.…”

Calcium channel gating

“…Ben-Johny et al [11]). Quantification of current kinetics and steady state activation of CaV1.2 by Beyl et al [16] revealed the following sequence of events: At rest, the voltage sensors (VSs) are pulled into a down position by the electrical field.…”