Restoration of Normal L-Type Ca ²⁺ Channel Function During Timothy Syndrome by Ablation of an Anchoring Protein

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 CaV1.2-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 CaV1.2-LQT8 channel gating may constitute a novel general mechanism for CaV1.2-driven arrhythmias.

Nitric Oxide–Dependent Feedback Loop Regulates Transient Receptor Potential Vanilloid 4 (TRPV4) Channel Cooperativity and Endothelial Function in Small Pulmonary Arteries

“…Coupling coefficients for the coupling among TRPV4 channels at a cluster were determined using a coupled Markov chain model in MATLAB, as previously described 5, 31, 32, 33, 34. [F‐F 0 ]/F 0 traces showing steady baseline (ie, at least 30 s duration) were selected for analyzing the cooperative gating of TRPV4 channels.…”

Hyperactivation of L-type voltage-gated Ca2+ channels in C. elegans striated muscle can result from point mutations in the IS6 or the IIIS4 segment of the α1 subunit.

“…In particular, the distal C-terminal domain of L-type channels may act as a transcriptional regulator. The cleavage of this domain is thought to be Ca 2+ dependent, and the resulting transcription factor has been shown to modulate the transcription of several genes, including the gene encoding the L-type α 1 subunit itself (GomezOspina et al, 2006;Schroder et al, 2009 (Cheng et al, 2011). We believe that identification of new partners of this channel could lead to novel therapeutics targets for treating pathologies involving L-type channels, such as hypoPP or Timothy syndrome.…”

“…Until now, very few of these studies have been published. Cheng et al have described that the inactivation kinetics of the current is strongly slowed in mice carrying the Timothy syndrome mutation G406R (Cheng et al, 2011). Wu et al have shown that skeletal muscle fibers of mice carrying the hypoPP mutation R528H exhibit an anomalous leak current through the mutated S4 segments (Wu et al, 2012).…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…Thus, the patients’ ECG showed a prolonged QT interval leading to death from cardiac arrhythmia [66]. Interestingly, this mutant Ca V 1.2 channel function could be modulated by one anchoring protein AKAP150, elimination of which could abrogate the prolonged QT interval [71], implying AKAP150 may be a promising target for TS.…”