Journal
HEART RHYTHM
Volume 14, Issue 3, Pages 432-439Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.hrthm.2016.12.013
Keywords
[Ca2+](i) transients; Ventricular myocytes; Patch-damp technique; Cell shortening; L-type calcium current; PKA signaling; Calcitriol
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Funding
- Ministerio de Economia y Competitividad (MINECO) [SAF2014-57190R]
- Instituto de Salud Carlos III [PI14/01078]
- European Regional Development Fund (FEDER)
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BACKGROUND Calcitriol, the bioactive metabolite of vitamin D, exerts its effects through interaction with the nuclear vitamin D receptor (VDR) to induce genomic responses. Calcitriol may also induce rapid responses via plasma membrane-associated VDR, involving the activation of second messengers and modulation of voltage-dependent channels. VDR is expressed in cardiomyocytes, but the molecular and cellular mechanisms involved in the rapid responses of calcitriol in the heart are poorly understood. OBJECTIVE The aim of the present study was to analyze the rapid nongenomic effect of calcitriol on L-type calcium channels, intracellular Ca2+ ([Ca2+]i) transients, and cell contractility in ventricular myocytes. METHODS We used the whole-cell patch-damp technique to record L-type calcium current (I-caL) and confocal microscopy to study global [Ca2+]; transients evoked by electrical stimulation and cell shortening in adult mouse ventricular myocytes treated with vehicle or with calcitriol. In some experiments, I-ca L was recorded using the perforated patch-damp technique. RESULTS Calcitriol treatment of cardiomyocytes induced a concentration -dependent increase in I-caL density (Half maximal effective concentration (EC50) = 0.23 nM) and a significant increase in peak [Ca2+]; transients and cell contraction. The effect of calcitriol on I-caL was prevented by pretreatment of cardiomyocytes with the protein kinase A (PKA) inhibitor KT-5720 but not with the beta-adrenergic Mocker propranolol. The effect of calcitriol on I-cal was absent in myocytes isolated from VDR knockout mice. CONCLUSION Calcitriol induces a rapid response in mouse ventricular myocytes that involves a VDR-PKA-dependent increase in (IcaL) density, enhancing [Ca2+]; transients and contraction.
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