Cooperative and acute inhibitionby multiple C-terminal motifs of L-type Ca2+ channels

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Abstract

Inhibitions and antagonists of L-type Ca²⁺ channels are important to both research and therapeutics. Here, we report C-terminus mediated inhibition (CMI) for Ca_V1.3 that multiple motifs coordinate to tune down Ca²⁺ current and Ca²⁺ influx toward the lower limits determined by end-stage CDI (Ca²⁺-dependent inactivation). Among IQV (preIQ3-IQ domain), PCRD and DCRD (proximal or distal C-terminal regulatory domain), spatial closeness of any two modules, e.g., by constitutive fusion, facilitates the trio to form the complex, compete against calmodulin, and alter the gating. Acute CMI by rapamycin-inducible heterodimerization helps reconcile the concurrent activation/inactivation attenuations to ensure Ca²⁺ influx is reduced, in that Ca²⁺ current activated by depolarization is potently (~65%) inhibited at the peak (full activation), but not later on (end-stage inactivation, ~300 ms). Meanwhile, CMI provides a new paradigm to develop Ca_V1 inhibitors, the therapeutic potential of which is implied by computational modeling of Ca_V1.3 dysregulations related to Parkinson's disease.

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Nan Liu

X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9606-4732
Yaxiong Yang

X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Lin Ge

X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Min Liu

X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Henry M Colecraft

Department of Physiology and Cellular Biophysics, Columbia University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Xiaodong Liu

X-Lab for Transmembrane Signaling Research, Department of Biomedical Engineering, Tsinghua University, Beijing, China

For correspondence
liuxiaodong@tsinghua.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3171-9611

Funding

National Natural Science Foundation of China (81171382,31370822,81371604)

Xiaodong Liu

Natural Science Foundation of Beijing Municipality (7142089)

Xiaodong Liu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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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.