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

Edward P. Cheng, Can Yuan, Manuel F. Navedo, Rose E. Dixon, Madeline Nieves-Cintrón, John D. Scott, Luis F. Santana

Research output: Contribution to journalArticle

62 Scopus citations

Abstract

Rationale: L-type Ca2+ (CaV1.2) 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 CaV1.2 channels causes long QT syndrome 8 (LQT8), a disease also known as Timothy syndrome. However, the mechanisms by which this mutation enhances CaV1.2-LQT8 currents and generates lethal arrhythmias are unclear. Objective: To test the hypothesis that the anchoring protein AKAP150 modulates CaV1.2-LQT8 channel gating in ventricular myocytes. Methods and Results: Using a combination of molecular, imaging, and electrophysiological approaches, we discovered that CaV1.2-LQT8 channels are abnormally coupled to AKAP150. A pathophysiological consequence of forming this aberrant ion channel-anchoring protein complex is enhanced Ca V1.2-LQT8 currents. This occurs through a mechanism whereby the anchoring protein functions like a subunit of CaV1.2-LQT8 channels that stabilizes the open conformation and augments the probability of coordinated openings of these channels. Ablation of AKAP150 restores normal gating in CaV1.2-LQT8 channels and protects the heart from arrhythmias. Conclusion: We propose that AKAP150-dependent changes in Ca V1.2-LQT8 channel gating may constitute a novel general mechanism for CaV1.2-driven arrhythmias.

Original languageEnglish (US)
Pages (from-to)255-261
Number of pages7
JournalCirculation Research
Volume109
Issue number3
DOIs
StatePublished - Jul 22 2011
Externally publishedYes

Keywords

  • arrhythmias
  • Ca1.2 channels
  • calcium
  • EC coupling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Restoration of normal L-type Ca<sup>2+</sup> channel function during timothy syndrome by ablation of an anchoring protein'. Together they form a unique fingerprint.

  • Cite this