|Título||Restoration of normal L-type Ca2+ channel function during Timothy syndrome by ablation of an anchoring protein.|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Autores||Cheng, EP, Yuan, C, Navedo, MF, Dixon, RE, Nieves-Cintrón, M, Scott, JD, Santana, LF|
|Date Published||2011 Jul 22|
|Palabras clave||A 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|
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.
|Alternate Journal||Circ. Res.|
|PubMed Central ID||PMC3151468|
|Grant List||R01 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