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 language | English (US) |
|---|---|
| Pages (from-to) | 1749-1754 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 109 |
| Issue number | 5 |
| DOIs | |
| State | Published - Jan 31 2012 |
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Keywords
- Calcium sparklets
- Coupled gating
- EC coupling
- Voltage-gated calcium channels
ASJC Scopus subject areas
- General
Cite this
Ca 2+ signaling amplification by oligomerization of L-type Ca v1.2 channels. / Dickson, Rose Ellen; Yuan, Can; Cheng, Edward P.; Navedo, Manuel F; Santana, Luis Fernando.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 5, 31.01.2012, p. 1749-1754.Research output: Contribution to journal › Article
}
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 -