Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein.

Imagen de Manuel F Navedo
TítuloRestoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein.
Publication TypeJournal Article
Year of Publication2011
AutoresCheng, EP, Yuan, C, Navedo, MF, Dixon, RE, Nieves-Cintrón, M, Scott, JD, Santana, LF
JournalCirc Res
Volume109
Issue3
Pagination255-61
Date Published2011 Jul 22
ISSN1524-4571
Palabras claveA Kinase Anchor Proteins, Action Potentials, Age Factors, Animals, Arrhythmias, Cardiac, Calcium, Calcium Channels, L-Type, Cardiomegaly, Ion Channel Gating, Long QT Syndrome, Mice, Mice, Transgenic, Myocardial Contraction, Myocytes, Cardiac, Protein Interaction Domains and Motifs, Syndactyly
Abstract

RATIONALE: L-type Ca(2+) (Ca(V)1.2) channels shape the cardiac action potential waveform and are essential for excitation-contraction coupling in heart. A gain-of-function G406R mutation in a cytoplasmic loop of Ca(V)1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances Ca(V)1.2-LQT8 currents and generates lethal arrhythmias are unclear.

OBJECTIVE: To test the hypothesis that the anchoring protein AKAP150 modulates Ca(V)1.2-LQT8 channel gating in ventricular myocytes.

METHODS AND RESULTS: Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that Ca(V)1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca(V)1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of Ca(V)1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in Ca(V)1.2-LQT8 channels and protects the heart from arrhythmias.

CONCLUSION: We propose that AKAP150-dependent changes in Ca(V)1.2-LQT8 channel gating may constitute a novel general mechanism for Ca(V)1.2-driven arrhythmias.

DOI10.1161/CIRCRESAHA.111.248252
Alternate JournalCirc. Res.
PubMed ID21700933
PubMed Central IDPMC3151468
Grant ListR01 HL085686 / HL / NHLBI NIH HHS / United States
R01 HL085686-05 / HL / NHLBI NIH HHS / United States
R01 HL085870 / HL / NHLBI NIH HHS / United States
R01 HL085870-05 / HL / NHLBI NIH HHS / United States
R01 HL088366 / HL / NHLBI NIH HHS / United States
R01 HL088366-06 / HL / NHLBI NIH HHS / United States
R01 HL098200 / HL / NHLBI NIH HHS / United States
R37 GM048231 / GM / NIGMS NIH HHS / United States
T32 GM007266 / GM / NIGMS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States