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

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 (I_CaL) 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, I_CaL was recorded using the perforated patch-clamp 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⁺]_i 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 β-adrenergic blocker 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 I_CaL density, enhancing [Ca²⁺]_i transients and contraction.