Ca2+ signaling amplification by oligomerization of L-type Cav1.2 channels.

Imagen de Manuel F Navedo
TítuloCa2+ signaling amplification by oligomerization of L-type Cav1.2 channels.
Publication TypeJournal Article
Year of Publication2012
AutoresDixon, RE, Yuan, C, Cheng, EP, Navedo, MF, Santana, LF
JournalProc Natl Acad Sci U S A
Volume109
Issue5
Pagination1749-54
Date Published2012 Jan 31
ISSN1091-6490
Palabras claveAnimals, Biopolymers, Calcium Channels, L-Type, Calcium Signaling, Heart Ventricles, Ion Channel Gating, Mutation
Abstract

Ca(2+) influx via L-type Ca(v)1.2 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(v)1.2 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(v)1.2 channels with Ca(v)1.2 channels carrying a gain-of-function mutation that causes arrhythmias and autism in humans with Timothy syndrome (Ca(v)1.2-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(v)1.2-TS increasing the activity of adjoining WT Ca(v)1.2 channels. Collectively, these data support the concept that oligomerization of Ca(v)1.2 channels via their C termini can result in the amplification of Ca(2+) influx into excitable cells.

DOI10.1073/pnas.1116731109
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22307641
PubMed Central IDPMC3277143
Grant ListHL085686 / HL / NHLBI NIH HHS / United States
HL085870 / HL / NHLBI NIH HHS / United States
HL098200 / HL / NHLBI NIH HHS / United States
R01 HL085686 / HL / NHLBI NIH HHS / United States
R01 HL085870 / HL / NHLBI NIH HHS / United States
R01 HL098200 / HL / NHLBI NIH HHS / United States
T32 GM007266 / GM / NIGMS NIH HHS / United States