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Calcitriol (1,25-dihydroxyvitamin D3) increases L-type calcium current via protein kinase A signaling and modulates calcium cycling and contractility in isolated mouse ventricular myocytes

AuthorsTamayo, María; Manzanares, Esmeralda; Bas, Manuel; Martín-Nunes, Laura; Val-Blasco, Almudena; Larriba, María Jesús ; Fernández-Velasco, María ; Delgado, Carmen
Keywords[Ca2+]i transients
Ventricular myocytes
Patch-clamp technique
Cell shortening
L-type calcium current
PKA signaling
Issue Date2017
CitationHeart Rhythm 14(3): 432-439 (2017)
Abstract[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-clamp technique to record L-type calcium current (ICaL) and confocal microscopy to study global [Ca2+]i transients evoked by electrical stimulation and cell shortening in adult mouse ventricular myocytes treated with vehicle or with calcitriol. In some experiments, ICaL was recorded using the perforated patch-clamp technique.
[Results]: Calcitriol treatment of cardiomyocytes induced a concentration-dependent increase in ICaL density (Half maximal effective concentration (EC50) = 0.23 nM) and a significant increase in peak [Ca2+]i transients and cell contraction. The effect of calcitriol on ICaL was prevented by pretreatment of cardiomyocytes with the protein kinase A (PKA) inhibitor KT-5720 but not with the β-adrenergic blocker propranolol. The effect of calcitriol on ICaL 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+]i transients and contraction.
Publisher version (URL)https://doi.org/10.1016/j.hrthm.2016.12.013
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