Impaired CaV1.2 inactivation reduces the efficacy of calcium channel blockers in the treatment of LQT8

Mutations in the CaV1.2 L-type calcium channel can cause a profound form of long-QT syndrome known as long-QT type 8 (LQT8), which results in cardiac arrhythmias that are often fatal in early childhood. A growing number of such pathogenic mutations in CaV1.2 have been identified, increasing the need...

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Bibliographic Details
Published in:Journal of molecular and cellular cardiology 2022-12, Vol.173, p.92-100
Main Authors: Bamgboye, Moradeke A., Traficante, Maria K., Owoyemi, Josiah, DiSilvestre, Deborah, Vieira, Daiana C.O., Dick, Ivy E.
Format: Article
Language:English
Subjects:
Channelopathy
Ion channel
Long-QT syndrome
Voltage-gated calcium channel
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Summary:Mutations in the CaV1.2 L-type calcium channel can cause a profound form of long-QT syndrome known as long-QT type 8 (LQT8), which results in cardiac arrhythmias that are often fatal in early childhood. A growing number of such pathogenic mutations in CaV1.2 have been identified, increasing the need for targeted therapies. As many of these mutations reduce channel inactivation; resulting in excess Ca2+ entry during the action potential, calcium channel blockers (CCBs) would seem to represent a promising treatment option. Yet CCBs have been unsuccessful in the treatment of LQT8. Here, we demonstrate that this lack of efficacy likely stems from the impact of the mutations on CaV1.2 channel inactivation. As CCBs are known to preferentially bind to the inactivated state of the channel, mutation-dependent deficits in inactivation result in a decrease in use-dependent block of the mutant channel. Further, application of the CCB verapamil to induced pluripotent stem cell (iPSC) derived cardiomyocytes from an LQT8 patient demonstrates that this loss of use-dependent block translates to a lack of efficacy in correcting the LQT phenotype. As a growing number of channelopathic mutations demonstrate effects on channel inactivation, reliance on state-dependent blockers may leave a growing population of patients without a viable treatment option. This biophysical understanding of the interplay between inactivation deficits and state-dependent block may provide a new avenue to guide the development of improved therapies. [Display omitted] •Gating changes due to LQT8 mutations in CaV1.2 reduce the use-dependent block of verapamil.•The loss of use-dependent block by verapamil likely extends to other calcium channel blockers including DHPs.•Decreased inactivation of CaV1.2 appears to be a general mechanism for decreased verapamil efficacy.•Decreased verapamil efficacy translates to decreased AP shortening in LQT8 iPSC derived cardiomyocytes.
ISSN:0022-2828
1095-8584
1095-8584
DOI:10.1016/j.yjmcc.2022.10.003