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Review
. 2015;8(2):188-205.
doi: 10.2174/1874467208666150507110359.

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

Manu Ben-Johny, Ivy E Dick, Lingjie Sang, Worawan B Limpitikul, Po Wei Kang, Jacqueline Niu, Rahul Banerjee, Wanjun Yang, Jennifer S Babich, John B Issa, Shin Rong Lee, Ho Namkung, Jiangyu Li, Manning Zhang, Philemon S Yang, Hojjat Bazzazi, Paul J Adams, Rosy Joshi-Mukherjee, Daniel N Yue, David T Yue  1
Affiliations
Review

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

Manu Ben-Johny et al. Curr Mol Pharmacol. 2015.

Abstract

Voltage-gated Na and Ca(2+) 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 Ca(2+) 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.

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Figures

Figure (1)
Figure (1)
A) Convenient experimental setup to examine CDI of Ca2+ channels. Left, no feedback regulation triggered upon Ba2+ influx through channel. Right, Ca2+ influx triggers Ca2+ regulation. B) Typical Ca2+ and Ba2+ current profiles through CaV1.3 channel. In response to a step depolarization, the Ca2+ current (red trace) activates and then sharply inactivates. Ba2+ current (black trace), does not inactivate. Adapted with permission [115]. C) Diagram depicting regions of Ca2+ channels critical for calmodulation, including dual vestigial EF hands (pink and green), IQ region (blue) on the C-terminus and NSCaTE (black) on the N-terminus of the channel. D) Mechanist scheme for CaM regulation of Ca2+ channels. In the E state, the channel is devoid of CaM and incapable of undergoing CDI. Following apoCaM binding (A state), the channel can undergo N- or C-lobe-driven CDI, state IN and IC, respectively. Configuration ICN corresponds to a fully inactivated state where N-and C-lobe of CaM engages respective effector interfaces. E) Molecular model of apoCaM preassociation to CaV1.3. The N-lobe of apoCaM preassociates with the dual vestigial EF hand segments, and the C-lobe with the channel IQ domain. F) Proposed model of Ca2+/CaM interaction with channel interfaces. Upon Ca2+ binding, the N-lobe of Ca2+/CaM interacts with the NSCaTE segment. The C-lobe of Ca2+/CaM forms a tripartite complex with the channel dual vestigial EF hands and the IQ domain. Adapted with permission [41].
Figure (2)
Figure (2)
A) Functional bipartition of CaM in CaV2.1 channel. Top, CaV2.1 currents evoked by a train of action potentials. Rapid Ca2+ dependent facilation of Ca2+ current (circle, bottom subpanel) is followed by Ca2+-dependent inactivation (square, bottom subpanel). Adapted with permission [70]. B) Distinct modes of spatial Ca2+ signaling. Under high Ca2+ buffering, Ca2+ elevations are restricted to the channel nanodomain (left). Low Ca2+ buffering permits global elevation of cytoplasmic Ca2+ (right). The resident CaM molecule can decode these distinct Ca2+ signals Adapted with permission [83]. C) Table summarizes dual regulation of CaV channels by the two lobes of CaM. Adapted with permission [16].
Figure (3)
Figure (3)
A) Milestones in Na channel (left) and Ca2+ channel (right) calmodulation. B) Experimental scheme to study Ca2+ regulation of Na channels. Na current properties are evaluated from two population of cells dialyzed internal solutions containing either low and high Ca2+ concentrations C). Protocol used to determine steady-state inactivation of Na channels (left). Expected Ca2+ dependent effects for two well-studied Na channel families. Adapted with permission [115].
Figure (4)
Figure (4)
A) Na channel regulation probed using rapid delivery of Ca2+ by photouncaging. Schematic shows simultaneous patch-fluorimetry and Ca2+ photouncaging. Ca2+ measured quantitatively using ratiometric fluorescence measurement. Ca2+ elevations are triggered using a brief UV pulse. B) Absence of Ca2+ regulation of cardiac Na channels (NaV1.5) in a heterologous (HEK293) system. C) Ca2+ regulation of native NaV1.5 current from ventricular myocytes. D) Robust Ca2+-dependent inactivation in heterologously expressed NaV1.4 channels. Here, intracellular Ca2+ elevation decreases peak Na current (second row). Population data shows a dose-dependent response of CDI to intracellular Ca2+ (bottom). E) Robust Ca2+-dependent inactivation of native NaV1.4 currents from skeletal myotubes (GLT cells). Adapted with permission [115].
Figure (5)
Figure (5)
A) Table shows conservation of Ca2+/CaM regulation of Ca2+ and Na channels. B) Phylogenetic tree of the Ca2+ and Na channel superfamilies. HVA, high-voltage activated Ca2+ channels. LVA, low-voltage activated Ca2+ channels. C) Modularity of CI region. Transplanting CI region of NaV1.4 to CaV1.3 supports CDI. Coexpression of mutant CaM1234 abolishes Ca2+ regulation of these chimeric channels. Adapted with permission [115].
Fig. (6)
Fig. (6)
A) Sequence alignment of the two lobes of CaM. The EF hand segments are shaded rose and green. LQTS-associated CaM mutations are highlighted. B) Reduction of CDI of Ca2+ currents in adult guinea pig ventricular myocytes (aGPVMs) expressing CaMD96V (red), compared to CaMWT (black). Ba2+ current through the same channels (gray) shows the extent of VDI in these cells. C) Averaged action potentials from aGPVMs expressing CaMWT (black) and CaMD96V (red). Shaded regions represent standard deviation. CaMD96V significantly prolongs the APD. D) Averaged Ca2+ transient waveforms from aGPVMs expressing CaMWT (black) and CaMD96V (red). Shaded regions represent standard deviation. CaMD96V significantly increases the Ca2+ transient magnitude. Adapted with permission [155].
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