The role of coupled gating of L-type calcium channels in arrhythmogenesis in Timothy syndrome (LQT8)

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The role of coupled gating of L-type calcium channels in arrhythmogenesis in Timothy syndrome (LQT8)

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dc.contributor.advisor Santana, Luis F en_US Cheng, Edward Peiyang en_US 2012-09-10T18:30:18Z 2012-09-10 2012 en_US
dc.identifier.other Cheng_washington_0250E_10279.pdf en_US
dc.description Thesis (Ph.D.)--University of Washington, 2012 en_US
dc.description.abstract L-type Ca<super>2+</super> (Ca<sub>V</sub>1.2) channels shape the cardiac action potential waveform and are essential for excitation-contraction (EC) coupling in the heart. We find that a transient subpopulation of 2 to 6 Ca<sub>V</sub>1.2 channels gate concertedly via a novel coupled gating modality. In the presence of the scaffolding protein AKAP150: PKC&alpha, calmodulin inhibition, and the G406R mutation that causes Timothy syndrome (TS), also known as long QT syndrome type 8 (LQT8), increase the probability of coupled gating. As for the mechanism of coupled gating, we propose that Ca<sub>V</sub>1.2 channels interact with each other via their carboxy tails when calmodulin is dislodged from the IQ domain, and coupled gating requires AKAP150 to bind to the Ca<sub>V</sub>1.2 carboxy tails via its leucine zipper domain and to act as a scaffold. To study further the role of coupled gating and AKAP150 in arrhythmogenesis in LQT8, we created a LQT8 transgenic mouse expressing cardiac-specific Ca<sub>V</sub>1.2-LQT8-tRFP channels. Importantly, we then crossed these LQT8 transgenics with AKAP150<super>-/-</super> mice, and the LQT8/ AKAP150<super>-/-</super> mice show a rescue of the wild-type (WT) phenotype. Compared to WT and LQT8/ AKAP150<super>-/-</super> ventricular myocytes, LQT8 ventricular myocytes have delayed inactivation in whole-cell I<sub>Ca</sub>, and there is increased frequency in coupled gating and open time in cell-attached i<sub>Ca</sub>. These myocytes also have prolonged action potential duration and arrhythmogenic voltage fluctuations, such as early and delayed afterdepolarizations. With respect to EC coupling, LQT8 ventricular myocytes have increased [Ca<super>2+</super>] transient amplitudes and more frequent arrhythmogenic spontaneous Ca<super>2+</super> releases. On the whole animal level, LQT8 mice have prolonged QTC interval and more frequent incidence of Torsades de Pointes ventricular tachycardia than WT or LQT8/ AKAP150<super>-/-</super>. In conclusion, AKAP150 mediated coupled gating of Ca<sub>V</sub>1.2 channels plays a central role in the pathophysiology of LQT8, causing local perturbation on EC coupling that lead to arrhythmogenesis. en_US
dc.format.mimetype application/pdf en_US
dc.language.iso en_US en_US
dc.subject arrhythmias; calcium; CaV1.2 channels; EC coupling; LQT8; Timothy syndrome en_US
dc.subject.other Physiology en_US
dc.subject.other Biophysics en_US
dc.subject.other Physiology and biophysics en_US
dc.title The role of coupled gating of L-type calcium channels in arrhythmogenesis in Timothy syndrome (LQT8) en_US
dc.type Thesis en_US
dc.embargo.terms Delay release for 2 years -- then make Open Access en_US
dc.embargo.lift 2014-08-31T18:30:18Z

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