title: Decrease in the density of t-tubular L-type Ca2+ channel currents in failing ventricular myocytes.
abstract: In some forms of cardiac hypertrophy and failure, the gain of Ca(2+)-induced Ca(2+) release [CICR; i.e., the amount of Ca(2+) released from the sarcoplasmic reticulum normalized to Ca(2+) influx through L-type Ca(2+) channels (LTCCs)] decreases despite the normal whole cell LTCC current density, ryanodine receptor number, and sarcoplasmic reticulum Ca(2+) content. This decrease in CICR gain has been proposed to arise from a change in dyad architecture or derangement of the t-tubular (TT) structure. However, the activity of surface sarcolemmal LTCCs has been reported to increase despite the unaltered whole cell LTCC current density in failing human ventricular myocytes, indicating that the "decreased CICR gain" may reflect a decrease in the TT LTCC current density in heart failure. Thus, we analyzed LTCC currents of failing ventricular myocytes of mice chronically treated with isoproterenol (Iso). Although Iso-treated mice exhibited intact t-tubules and normal LTCC subunit expression, acute occlusion of t-tubules of isolated ventricular myocytes with osmotic shock (detubulation) revealed that the TT LTCC current density was halved in Iso-treated versus control myocytes. Pharmacological analysis indicated that kinases other than PKA or Ca(2+)/calmodulin-dependent protein kinase II insufficiently activated, whereas protein phosphatase 1/2A excessively suppressed, TT LTCCs in Iso-treated versus control myocytes. These results indicate that excessive β-adrenergic stimulation causes the decrease in TT LTCC current density by altering the regulation of TT LTCCs by protein kinases and phosphatases in heart failure. This phenomenon might underlie the decreased CICR gain in heart failure.
authors.affiliation: Department of Anatomy and Molecular Pharmacology, Shinshu University School of Medicine, Nagano, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Horiuchi-Hirose
authors.forename: Toshihide
authors.initials: T
authors.lastname: Kashihara
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakada
authors.forename: Nagomi
authors.initials: N
authors.lastname: Kurebayashi
authors.forename: Hisashi
authors.initials: H
authors.lastname: Shimojo
authors.forename: Toshihide
authors.initials: T
authors.lastname: Shibazaki
authors.forename: Xiaona
authors.initials: X
authors.lastname: Sheng
authors.forename: Shiharu
authors.initials: S
authors.lastname: Yano
authors.forename: Masamichi
authors.initials: M
authors.lastname: Hirose
authors.forename: Minoru
authors.initials: M
authors.lastname: Hongo
authors.forename: Takashi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Moriizumi
authors.forename: Hideho
authors.initials: H
authors.lastname: Ueda
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006333:Heart Failure / Q000201:enzymology / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000201:enzymology / Q000502:physiology*; D010770:Phosphotransferases / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000502:physiology; D054648:Protein Phosphatase 2 / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D002316:Cardiotonic Agents; D010770:Phosphotransferases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D007545:Isoproterenol