Graded Ca2+/calmodulin-dependent coupling of voltage-gated CaV1.2 channels

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Abstract

In the heart, reliable activation of Ca²⁺ release from the sarcoplasmic reticulum during the plateau of the ventricular action potential requires synchronous opening of multiple Ca_V1.2 channels. Yet the mechanisms that coordinate this simultaneous opening during every heartbeat are unclear. Here, we demonstrate that Ca_V1.2 channels form clusters that undergo dynamic, reciprocal, allosteric interactions. This 'functional coupling' facilitates Ca²⁺ influx by increasing activation of adjoined channels and occurs through C-terminal-to-C-terminal interactions. These interactions are initiated by binding of incoming Ca²⁺ to calmodulin (CaM) and proceed through Ca²⁺/CaM binding to the Ca_V1.2 pre-IQ domain. Coupling fades as [Ca²⁺]_i decreases, but persists longer than the current that evoked it, providing evidence for 'molecular memory'. Our findings suggest a model for Ca_V1.2 channel gating and Ca²⁺-influx amplification that unifies diverse observations about Ca²⁺ signaling in the heart, and challenges the long-held view that voltage-gated channels open and close independently.

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Rose E Dixon

Department of Physiology and Biophysics, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Claudia M Moreno

Department of Physiology and Biophysics, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Can Yuan

Department of Physiology and Biophysics, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Ximena Opitz-Araya

Department of Physiology and Biophysics, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Marc D Binder

Department of Physiology and Biophysics, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Manuel F Navedo

Department of Pharmacology, University of California, Davis, Davis, United States

Competing interests
The authors declare that no competing interests exist.
Luis F Santana

Department of Physiology and Biophysics, University of Washington, Seattle, United States

For correspondence
santana@uw.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#3374-01) of the University of Washington.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.