Abstract
The spontaneous activity of sinoatrial node (SAN) pacemaker cells is generated by a functional interplay between the activity of ionic currents of the plasma membrane and intracellular Ca2+ dynamics. The molecular correlate of a dihydropyridine (DHP)-sensitive sustained inward Na+ current (Ist), a key player in SAN automaticity, is still unknown. Here we show that Ist and the L-type Ca2+ current (ICa,L) share CaV1.3 as a common molecular determinant. Patch-clamp recordings of mouse SAN cells showed that Ist is activated in the diastolic depolarization range, and displays Na+ permeability and minimal inactivation and sensitivity to ICa,L activators and blockers. Both CaV1.3-mediated ICa,L and Ist were abolished in CaV1.3-deficient (CaV1.3−/−) SAN cells but the CaV1.2-mediated ICa,L current component was preserved. In SAN cells isolated from mice expressing DHP-insensitive CaV1.2 channels (CaV1.2DHP−/−), Ist and CaV1.3-mediated ICa,L displayed overlapping sensitivity and concentration–response relationships to the DHP blocker nifedipine. Consistent with the hypothesis that CaV1.3 rather than CaV1.2 underlies Ist, a considerable fraction of ICa,L was resistant to nifedipine inhibition in CaV1.2DHP−/− SAN cells. These findings identify CaV1.3 channels as essential molecular components of the voltage-dependent, DHP-sensitive Ist Na+ current in the SAN.
Highlights
Share CaV1.3 as a common molecular determinant
The molecular correlates of most cardiac ionic currents have been identified allowing the development of genetically modified mouse models targeting specific ion channels including HCN4-7, 8, HCN2-If9, 10, CaV1.3-ICa,L11, 12, CaV3.1-ICa,T13 and Ncx1-INCX14
Ist is activated at low membrane voltages and supplies persistent inward current flowing over the full diastolic depolarization range
Summary
Patch-clamp recordings of mouse SAN cells showed that Ist is activated in the diastolic depolarization range, and displays Na+ permeability and minimal inactivation and sensitivity to ICa,L activators and blockers. Both CaV1.3-mediated ICa,L and Ist were abolished in CaV1.3-deficient (CaV1.3−/−) SAN cells but the CaV1.2-mediated ICa,L current component was preserved. Consistent with the hypothesis that CaV1.3 rather than CaV1.2 underlies Ist, a considerable fraction of ICa,L was resistant to nifedipine inhibition in CaV1.2DHP−/− SAN cells These findings identify CaV1.3 channels as essential molecular components of the voltage-dependent, DHPsensitive Ist Na+ current in the SAN. In addition to forming distinct types of ICa,L with different voltage dependencies of activation and inactivation, CaV1.3 and CaV1.2 channels are differentially localized in SAN cell membranes[25]
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