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Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel.

ABSTRACT: The L-type cardiac calcium channel (LTCC) plays a prominent role in the electric and mechanical function of the heart. Mutations in the LTCC have been associated with a number of inherited cardiac arrhythmia syndromes, including Timothy, Brugada, and early repolarization syndromes. Elucidation of the genetic defects associated with these syndromes has led to a better understanding of molecular and cellular mechanisms and the development of novel therapeutic approaches to dealing with the arrhythmic manifestations. This review provides an overview of the molecular structure and function of the LTCC, the genetic defects in these channels known to contribute to inherited disorders, and the underlying molecular and cellular mechanisms contributing to the development of life-threatening arrhythmias.

SUBMITTER: Napolitano C

PROVIDER: S-EPMC3056572 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel.

Napolitano Carlo C Antzelevitch Charles C Antzelevitch Charles C

Circulation research 20110301 5

The L-type cardiac calcium channel (LTCC) plays a prominent role in the electric and mechanical function of the heart. Mutations in the LTCC have been associated with a number of inherited cardiac arrhythmia syndromes, including Timothy, Brugada, and early repolarization syndromes. Elucidation of the genetic defects associated with these syndromes has led to a better understanding of molecular and cellular mechanisms and the development of novel therapeutic approaches to dealing with the arrhyth ...[more]

PMID: 21372292

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Project description:As with other elements of the peripheral auditory system, spiral ganglion neurons display specializations that vary as a function of location along the tonotopic axis. Previous work has shown that voltage-gated K(+) channels and synaptic proteins show graded changes in their density that confers rapid responsiveness to neurons in the high frequency, basal region of the cochlea and slower, more maintained responsiveness to neurons in the low frequency, apical region of the cochlea. In order to understand how voltage-gated calcium channels (VGCCs) may contribute to these diverse phenotypes, we identified the VGCC α-subunits expressed in the ganglion, investigated aspects of Ca(2+)-dependent neuronal firing patterns, and mapped the intracellular and intercellular distributions of seven VGCC α-subunits in the spiral ganglion in vitro. Initial experiments with qRT-PCR showed that eight of the ten known VGCC α-subunits were expressed in the ganglion and electrophysiological analysis revealed firing patterns that were consistent with the presence of both LVA and HVA Ca(2+) channels. Moreover, we were able to study seven of the α-subunits with immunocytochemistry, and we found that all were present in spiral ganglion neurons, three of which were neuron-specific (Ca(V)1.3, Ca(V)2.2, and Ca(V)3.3). Further characterization of neuron-specific α-subunits showed that Ca(V)1.3 and Ca(V)3.3 were tonotopically-distributed, whereas Ca(V)2.2 was uniformly distributed in apical and basal neurons. Multiple VGCC α-subunits were also immunolocalized to Schwann cells, having distinct intracellular localizations, and, significantly, appearing to distinguish putative compact (Ca(V)2.3, Ca(V)3.1) from loose (Ca(V)1.2) myelin. Electrophysiological evaluation of spiral ganglion neurons in the presence of TEA revealed Ca(2+) plateau potentials with slopes that varied proportionately with the cochlear region from which neurons were isolated. Because afterhyperpolarizations were minimal or absent under these conditions, we hypothesize that differential density and/or kinetics of one or more of the VGCC α-subunits could account for observed tonotopic differences. These experiments have set the stage for defining the clear multiplicity of functional control in neurons and Schwann cells of the spiral ganglion.

Dataset Information

Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel.

Publications

Phenotypical manifestations of mutations in the genes encoding subunits of the cardiac voltage-dependent L-type calcium channel.

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