Ca 2+ signaling amplification by oligomerization of L-type Ca v1.2 channels

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Ca 2+ influx via L-type Ca v1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca 2+ signals produced by the opening of these channels is a hallmark of many intracellular signaling cascades, including excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that Ca v1.2 channels form clusters of varied sizes in ventricular myocytes. Physical interaction between these channels via their C-tails renders them capable of coordinating their gating, thereby amplifying Ca 2+ influx and excitation-contraction coupling. Light-induced fusion of WT Ca v1.2 channels with Ca v1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca v1.2-TS) increased Ca 2+ currents, diastolic and systolic Ca 2+ levels, contractility and the frequency of arrhythmogenic Ca 2+ fluctuations in ventricular myocytes. Our data indicate that these changes in Ca 2+ signaling resulted from Ca v1.2-TS increasing the activity of adjoining WT Ca v1.2 channels. Collectively, these data support the concept that oligomerization of Ca v1.2 channels via their C termini can result in the amplification of Ca 2+ influx into excitable cells.

Original languageEnglish (US)
Pages (from-to)1749-1754
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number5
DOIs
StatePublished - Jan 31 2012

Fingerprint

Excitation Contraction Coupling
Muscle Cells
Optogenetics
Physiological Phenomena
Autistic Disorder
Tail
Cardiac Arrhythmias
Gene Expression
Light
Mutation
Timothy syndrome

Keywords

  • Calcium sparklets
  • Coupled gating
  • EC coupling
  • Voltage-gated calcium channels

ASJC Scopus subject areas

  • General

Cite this

@article{4b2805ecb1c842dc8c377136711aea61,
title = "Ca 2+ signaling amplification by oligomerization of L-type Ca v1.2 channels",
abstract = "Ca 2+ influx via L-type Ca v1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca 2+ signals produced by the opening of these channels is a hallmark of many intracellular signaling cascades, including excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that Ca v1.2 channels form clusters of varied sizes in ventricular myocytes. Physical interaction between these channels via their C-tails renders them capable of coordinating their gating, thereby amplifying Ca 2+ influx and excitation-contraction coupling. Light-induced fusion of WT Ca v1.2 channels with Ca v1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca v1.2-TS) increased Ca 2+ currents, diastolic and systolic Ca 2+ levels, contractility and the frequency of arrhythmogenic Ca 2+ fluctuations in ventricular myocytes. Our data indicate that these changes in Ca 2+ signaling resulted from Ca v1.2-TS increasing the activity of adjoining WT Ca v1.2 channels. Collectively, these data support the concept that oligomerization of Ca v1.2 channels via their C termini can result in the amplification of Ca 2+ influx into excitable cells.",
keywords = "Calcium sparklets, Coupled gating, EC coupling, Voltage-gated calcium channels",
author = "Dickson, {Rose Ellen} and Can Yuan and Cheng, {Edward P.} and Navedo, {Manuel F} and Santana, {Luis Fernando}",
year = "2012",
month = "1",
day = "31",
doi = "10.1073/pnas.1116731109",
language = "English (US)",
volume = "109",
pages = "1749--1754",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "5",

}

TY - JOUR

T1 - Ca 2+ signaling amplification by oligomerization of L-type Ca v1.2 channels

AU - Dickson, Rose Ellen

AU - Yuan, Can

AU - Cheng, Edward P.

AU - Navedo, Manuel F

AU - Santana, Luis Fernando

PY - 2012/1/31

Y1 - 2012/1/31

N2 - Ca 2+ influx via L-type Ca v1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca 2+ signals produced by the opening of these channels is a hallmark of many intracellular signaling cascades, including excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that Ca v1.2 channels form clusters of varied sizes in ventricular myocytes. Physical interaction between these channels via their C-tails renders them capable of coordinating their gating, thereby amplifying Ca 2+ influx and excitation-contraction coupling. Light-induced fusion of WT Ca v1.2 channels with Ca v1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca v1.2-TS) increased Ca 2+ currents, diastolic and systolic Ca 2+ levels, contractility and the frequency of arrhythmogenic Ca 2+ fluctuations in ventricular myocytes. Our data indicate that these changes in Ca 2+ signaling resulted from Ca v1.2-TS increasing the activity of adjoining WT Ca v1.2 channels. Collectively, these data support the concept that oligomerization of Ca v1.2 channels via their C termini can result in the amplification of Ca 2+ influx into excitable cells.

AB - Ca 2+ influx via L-type Ca v1.2 channels is essential for multiple physiological processes, including gene expression, excitability, and contraction. Amplification of the Ca 2+ signals produced by the opening of these channels is a hallmark of many intracellular signaling cascades, including excitation-contraction coupling in heart. Using optogenetic approaches, we discovered that Ca v1.2 channels form clusters of varied sizes in ventricular myocytes. Physical interaction between these channels via their C-tails renders them capable of coordinating their gating, thereby amplifying Ca 2+ influx and excitation-contraction coupling. Light-induced fusion of WT Ca v1.2 channels with Ca v1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca v1.2-TS) increased Ca 2+ currents, diastolic and systolic Ca 2+ levels, contractility and the frequency of arrhythmogenic Ca 2+ fluctuations in ventricular myocytes. Our data indicate that these changes in Ca 2+ signaling resulted from Ca v1.2-TS increasing the activity of adjoining WT Ca v1.2 channels. Collectively, these data support the concept that oligomerization of Ca v1.2 channels via their C termini can result in the amplification of Ca 2+ influx into excitable cells.

KW - Calcium sparklets

KW - Coupled gating

KW - EC coupling

KW - Voltage-gated calcium channels

UR - http://www.scopus.com/inward/record.url?scp=84857132094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857132094&partnerID=8YFLogxK

U2 - 10.1073/pnas.1116731109

DO - 10.1073/pnas.1116731109

M3 - Article

C2 - 22307641

AN - SCOPUS:84857132094

VL - 109

SP - 1749

EP - 1754

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 5

ER -