Key result
Inhibition of calcineurin by cyclosporine A or FK-506, or mutations in its binding site, significantly restored voltage-dependent inactivation in Timothy syndrome cardiac channels.
Why the study?
Does calcineurin inhibition improve voltage-dependent inactivation in Timothy syndrome cardiac channels?
Does calcineurin inhibition improve voltage-dependent inactivation in Timothy syndrome cardiac channels?
Calcineurin inhibition restores voltage-dependent inactivation in Timothy syndrome cardiac channels, identifying the CaN-binding site as a potential therapeutic target.
Answers are grounded in this paper and cite their sources.
Should not change clinical practice in Timothy syndrome; hypothesis-generating for CaN inhibition as a channelopathy target.
Ca(2+)-entry in the heart is tightly controlled by Cav1.2 inactivation, which involves Ca(2+)-dependent inactivation (CDI) and voltage-dependent inactivation (VDI) components. Timothy syndrome, a subtype-form of congenital long-QT syndrome, results from a nearly complete elimination of VDI by the G406R mutation in the α(1)1.2 subunit of Cav1.2. Here, we show that a single (A1929P) or a double mutation (H1926A-H1927A) within the CaN-binding site at the human C-terminal tail of α(1)1.2, accelerate the inactivation rate and enhances VDI of both wt and Timothy channels. These results identify the CaN-binding site as the long-sought VDI-regulatory motif of the cardiac channel. The substantial increase in VDI and the accelerated inactivation caused by the selective inhibitors of CaN, cyclosporine A and FK-506, which act at the same CaN-binding site, further support this conclusion. A reversal of enhanced-sympathetic tone by VDI-enhancing CaN inhibitors could be beneficial for improving Timothy syndrome complications such as long-QT and autism.
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Cohen-Kutner et al. (2012) studied Timothy syndrome. Calcineurin inhibitors (Cyclosporine A, FK-506) and CaN-binding site mutations vs. Untreated or wild-type channels was evaluated on Steady-state voltage-dependent inactivation (VDI) (p=<0.005). Inhibition of calcineurin by cyclosporine A or FK-506, or mutations in its binding site, significantly restored voltage-dependent inactivation in Timothy syndrome cardiac channels.
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