title: L-type Ca2+ channels serve as a sensor of the SR Ca2+ for tuning the efficacy of Ca2+-induced Ca2+ release in rat ventricular myocytes.
abstract: In cardiac excitation-contraction coupling, Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs), triggered by Ca2+ entry through the nearby L-type Ca2+ channel, induces Ca2+-dependent inactivation (CDI) of the Ca2+ channel. Aiming at elucidating the physiological role of CDI produced by CICR (CICR-dependent CDI), we investigated the contribution of the CICR-dependent CDI to action potential (AP) waveform and the amount of Ca2+-influx through Ca2+ channels during AP in rat ventricular myocytes. The elimination of the CICR-dependent CDI, by depletion of the SR Ca2+ with thapsigargin, significantly prolonged AP duration (APD). APD changed in parallel with the magnitude of CICR during the recovery of the SR Ca2+ content after transient depletion by caffeine. Such CICR-dependent change of APD persisted under the highly Ca2+ buffered condition where the Ca2+ signalling was restricted to nanoscale domains. Blockers of the Ca2+-dependent Cl- channel or the BK channel did not affect AP waveform. The amount of Ca2+-influx through Ca2+ channels during the SR-depleted type AP waveform, measured in the SR-depleted myocyte, was increased by 40 % over that during the SR-intact type AP waveform measured in the SR-intact myocyte. The protein kinase A stimulation further enhanced the Ca2+-influx during AP under the SR-depleted condition to 70 % of that under the SR-intact condition. These results indicate that the CICR-dependent CDI of L-type Ca2+ channels, under control of the privileged cross-signalling between L-type Ca2+ channels and RyRs, play important roles for monitoring and tuning the SR Ca2+ content via changes of AP waveform and the amount of Ca2+-influx during AP in ventricular myocytes.
authors.affiliation: Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences,University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. satomiaa@mol.f.u-tokyo.ac.jp
authors.forename: Hajime
authors.initials: H
authors.lastname: Takamatsu
authors.forename: Taku
authors.initials: T
authors.lastname: Nagao
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Satomi
authors.initials: S
authors.lastname: Adachi-Akahane
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology*; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002469:Cell Separation; D003600:Cytosol / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004594:Electrophysiology; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000502:physiology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D012964:Sodium / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D044169:Receptors, Calcium-Sensing; D004533:Egtazic Acid; D012964:Sodium; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium