title: 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.
abstract: 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.
  
  
  
  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.
  
  
  
  We used the whole-cell patch-clamp technique to record L-type calcium current (ICaL) and confocal microscopy to study global [Ca2+]itransients evoked by electrical stimulation and cell shortening in adult mouse ventricular myocytes treated with vehicle or with calcitriol. In some experiments, ICaLwas recorded using the perforated patch-clamp technique.
  
  
  
  Calcitriol treatment of cardiomyocytes induced a concentration-dependent increase in ICaLdensity (Half maximal effective concentration (EC50) = 0.23 nM) and a significant increase in peak [Ca2+]itransients and cell contraction. The effect of calcitriol on ICaLwas 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 ICaLwas absent in myocytes isolated from VDR knockout mice.
  
  
  
  Calcitriol induces a rapid response in mouse ventricular myocytes that involves a VDR-PKA-dependent increase in ICaLdensity, enhancing [Ca2+]itransients and contraction.
authors.affiliation: Biomedical Research Institute "Alberto Sols" CSIC-UAM, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Tamayo
authors.affiliation: Department of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Esmeralda
authors.initials: E
authors.lastname: Manzanares
authors.affiliation: Department of Pharmacology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Bas
authors.affiliation: Biomedical Research Institute "Alberto Sols" CSIC-UAM, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martín-Nunes
authors.affiliation: Instituto de Investigación Hospital Universitario La PAZ, Madrid, Spain.
authors.forename: Almudena
authors.initials: A
authors.lastname: Val-Blasco
authors.affiliation: Biomedical Research Institute "Alberto Sols" CSIC-UAM, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Jesús Larriba
authors.affiliation: Instituto de Investigación Hospital Universitario La PAZ, Madrid, Spain. Electronic address: maria.fernandez@idipaz.es.
authors.forename: María
authors.initials: M
authors.lastname: Fernández-Velasco
authors.affiliation: Biomedical Research Institute "Alberto Sols" CSIC-UAM, Madrid, Spain; Department of Pharmacology, School of Medicine, Complutense University, Madrid, Spain,. Electronic address: cdelgado@iib.uam.es.
authors.forename: Carmen
authors.initials: C
authors.lastname: Delgado
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D020013:Calcium Signaling / Q000187:drug effects*; D002227:Carbazoles / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056966:Excitation Contraction Coupling / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D018167:Receptors, Calcitriol / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D002227:Carbazoles; D004791:Enzyme Inhibitors; D011758:Pyrroles; D018167:Receptors, Calcitriol; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; D002117:Calcitriol
keywords: Calcitriol; Cell shortening; L-type calcium current; PKA signaling; Patch-clamp technique; Ventricular myocytes; [Ca(2+)](i) transients