title: Direct Evidence for Microdomain-Specific Localization and Remodeling of Functional L-Type Calcium Channels in Rat and Human Atrial Myocytes.
abstract: BACKGROUND
  Distinct subpopulations of L-type calcium channels (LTCCs) with different functional properties exist in cardiomyocytes. Disruption of cellular structure may affect LTCC in a microdomain-specific manner and contribute to the pathophysiology of cardiac diseases, especially in cells lacking organized transverse tubules (T-tubules) such as atrial myocytes (AMs).
  
  
  RESULTS
  Isolated rat and human AMs were characterized by scanning ion conductance, confocal, and electron microscopy. Half of AMs possessed T-tubules and structured topography, proportional to cell width. A bigger proportion of myocytes in the left atrium had organized T-tubules and topography than in the right atrium. Super-resolution scanning patch clamp showed that LTCCs distribute equally in T-tubules and crest areas of the sarcolemma, whereas, in ventricular myocytes, LTCCs primarily cluster in T-tubules. Rat, but not human, T-tubule LTCCs had open probability similar to crest LTCCs, but exhibited ≈ 40% greater current. Optical mapping of Ca(2+) transients revealed that rat AMs presented ≈ 3-fold as many spontaneous Ca(2+) release events as ventricular myocytes. Occurrence of crest LTCCs and spontaneous Ca(2+) transients were eliminated by either a caveolae-targeted LTCC antagonist or disrupting caveolae with methyl-β-cyclodextrin, with an associated ≈ 30% whole-cell ICa,L reduction. Heart failure (16 weeks post-myocardial infarction) in rats resulted in a T-tubule degradation (by ≈ 40%) and significant elevation of spontaneous Ca(2+) release events. Although heart failure did not affect LTCC occurrence, it led to ≈ 25% decrease in T-tubule LTCC amplitude.
  
  
  CONCLUSIONS
  We provide the first direct evidence for the existence of 2 distinct subpopulations of functional LTCCs in rat and human AMs, with their biophysical properties modulated in heart failure in a microdomain-specific manner.
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Glukhov
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Marina
authors.initials: M
authors.lastname: Balycheva
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Jose L
authors.initials: JL
authors.lastname: Sanchez-Alonso
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Zeki
authors.initials: Z
authors.lastname: Ilkan
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Anita
authors.initials: A
authors.lastname: Alvarez-Laviada
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Navneet
authors.initials: N
authors.lastname: Bhogal
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Ivan
authors.initials: I
authors.lastname: Diakonov
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Sophie
authors.initials: S
authors.lastname: Schobesberger
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Markus B
authors.initials: MB
authors.lastname: Sikkel
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Anamika
authors.initials: A
authors.lastname: Bhargava
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Faggian
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Prakash P
authors.initials: PP
authors.lastname: Punjabi
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.).
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: From Department of Cardiovascular Sciences, National Heart and Lung Institute, Imperial College London, United Kingdom (A.V.G., M.B., J.L.S.-A., Z.I., A.A.-L., N.B., I.D., S.S., M.B.S., A.B., P.P.P., J.G.); University of Verona, School of Medicine, Verona, Italy (M.B., G.F.); Department of Cardiothoracic Surgery, Hammersmith Hospital, National Heart and Lung Institute, Imperial College London, United Kingdom (P.P.P.); and Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, Philadelphia, PA (S.R.H.). j.gorelik@ic.ac.uk.
authors.forename: Julia
authors.initials: J
authors.lastname: Gorelik
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000032:analysis / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D006325:Heart Atria / Q000737:chemistry; D006801:Humans; D021962:Membrane Microdomains / Q000737:chemistry / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D013045:Species Specificity
chemical_list: D020746:Calcium Channels, L-Type
keywords: T-tubules; calcium channels; heart atria; heart failure; myocytes, cardiac; scanning ion conductance microscopy