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Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes.

ABSTRACT: Recent work has identified missense mutations in calmodulin (CaM) that are associated with severe early-onset long-QT syndrome (LQTS), leading to the proposition that altered CaM function may contribute to the molecular etiology of this subset of LQTS. To date, however, no experimental evidence has established these mutations as directly causative of LQTS substrates, nor have the molecular targets of CaM mutants been identified. Here, therefore, we test whether expression of CaM mutants in adult guinea-pig ventricular myocytes (aGPVM) induces action-potential prolongation, and whether affiliated alterations in the Ca(2+) regulation of L-type Ca(2+) channels (LTCC) might contribute to such prolongation. In particular, we first overexpressed CaM mutants in aGPVMs, and observed both increased action potential duration (APD) and heightened Ca(2+) transients. Next, we demonstrated that all LQTS CaM mutants have the potential to strongly suppress Ca(2+)/CaM-dependent inactivation (CDI) of LTCCs, whether channels were heterologously expressed in HEK293 cells, or present in native form within myocytes. This attenuation of CDI is predicted to promote action-potential prolongation and boost Ca(2+) influx. Finally, we demonstrated how a small fraction of LQTS CaM mutants (as in heterozygous patients) would nonetheless suffice to substantially diminish CDI, and derange electrical and Ca(2+) profiles. In all, these results highlight LTCCs as a molecular locus for understanding and treating CaM-related LQTS in this group of patients.

SUBMITTER: Limpitikul WB

PROVIDER: S-EPMC4262253 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes.

Limpitikul Worawan B WB Dick Ivy E IE Joshi-Mukherjee Rosy R Overgaard Michael T MT George Alfred L AL Yue David T DT

Journal of molecular and cellular cardiology 20140508

Recent work has identified missense mutations in calmodulin (CaM) that are associated with severe early-onset long-QT syndrome (LQTS), leading to the proposition that altered CaM function may contribute to the molecular etiology of this subset of LQTS. To date, however, no experimental evidence has established these mutations as directly causative of LQTS substrates, nor have the molecular targets of CaM mutants been identified. Here, therefore, we test whether expression of CaM mutants in adult ...[more]

PMID: 24816216

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Project description:Force-frequency relationships of isolated cardiac myocytes show complex behaviors that are thought to be specific to both the species and the conditions associated with the experimental preparation. Ca(2+) signaling plays an important role in shaping the force-frequency relationship, and understanding the properties of the force-frequency relationship in vivo requires an understanding of Ca(2+) dynamics under physiologically relevant conditions. Ca(2+) signaling is itself a complicated process that is best understood on a quantitative level via biophysically based computational simulation. Although a large number of models are available in the literature, the models are often a conglomeration of components parameterized to data of incompatible species and/or experimental conditions. In addition, few models account for modulation of Ca(2+) dynamics via ?-adrenergic and calmodulin-dependent protein kinase II (CaMKII) signaling pathways even though they are hypothesized to play an important regulatory role in vivo. Both protein-kinase-A and CaMKII are known to phosphorylate a variety of targets known to be involved in Ca(2+) signaling, but the effects of these pathways on the frequency- and inotrope-dependence of Ca(2+) dynamics are not currently well understood. In order to better understand Ca(2+) dynamics under physiological conditions relevant to rat, a previous computational model is adapted and re-parameterized to a self-consistent dataset obtained under physiological temperature and pacing frequency and updated to include ?-adrenergic and CaMKII regulatory pathways. The necessity of specific effector mechanisms of these pathways in capturing inotrope- and frequency-dependence of the data is tested by attempting to fit the data while including and/or excluding those effector components. We find that: (1) ?-adrenergic-mediated phosphorylation of the L-type calcium channel (LCC) (and not of phospholamban (PLB)) is sufficient to explain the inotrope-dependence; and (2) that CaMKII-mediated regulation of neither the LCC nor of PLB is required to explain the frequency-dependence of the data.

Dataset Information

Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes.

Publications

Calmodulin mutations associated with long QT syndrome prevent inactivation of cardiac L-type Ca(2+) currents and promote proarrhythmic behavior in ventricular myocytes.

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