title: Tail-anchored membrane protein SLMAP is a novel regulator of cardiac function at the sarcoplasmic reticulum.
abstract: Sarcolemmal membrane-associated proteins (SLMAPs) are components of cardiac membranes involved in excitation-contraction (E-C) coupling. Here, we assessed the role of SLMAP in cardiac structure and function. We generated transgenic (Tg) mice with cardiac-restricted overexpression of SLMAP1 bearing the transmembrane domain 2 (TM2) to potentially interfere with endogenous SLMAP through homodimerization and subcellular targeting. Histological examination revealed vacuolated myocardium; the severity of which correlated with the expression level of SLMAP1-TM2. High resolution microscopy showed dilation of the sarcoplasmic reticulum/endoplasmic reticulum (SR/ER) and confocal imaging combined with biochemical analysis indicated targeting of SLMAP1-TM2 to the SR/ER membranes and inappropriate homodimerization. Older (28 wk of age) Tg mice exhibited reduced contractility with impaired relaxation as assessed by left ventricle pressure monitoring. The ventricular dysfunction was associated with electrophysiological abnormalities (elongated QT interval). Younger (5 wk of age) Tg mice also exhibited an elongated QT interval with minimal functional disturbances associated with the activation of the fetal gene program. They were less responsive to isoproterenol challenge (ΔdP/dt(max)) and developed electrical and left ventricular pressure alternans. The altered electrophysiological and functional disturbances in Tg mice were associated with diminished expression level of calcium cycling proteins of the sarcoplasmic reticulum such as the ryanodine receptor, Ca(2+)-ATPase, calsequestrin, and triadin (but not phospholamban), as well as significantly reduced calcium uptake in microsomal fractions. These data demonstrate that SLMAP is a regulator of E-C coupling at the level of the SR and its perturbation results in progressive deterioration of cardiac electrophysiology and function.
authors.affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Moni
authors.initials: M
authors.lastname: Nader
authors.forename: Bart
authors.initials: B
authors.lastname: Westendorp
authors.forename: Omar
authors.initials: O
authors.lastname: Hawari
authors.forename: Maysoon
authors.initials: M
authors.lastname: Salih
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Frans H H
authors.initials: FH
authors.lastname: Leenen
authors.forename: Balwant S
authors.initials: BS
authors.lastname: Tuana
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis; D002155:Calsequestrin / Q000096:biosynthesis; D002352:Carrier Proteins / Q000096:biosynthesis; D005260:Female; D006321:Heart / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000096:biosynthesis; D009200:Myocardial Contraction / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000096:biosynthesis; D012519:Sarcoplasmic Reticulum / Q000378:metabolism / Q000502:physiology*
chemical_list: D000318:Adrenergic beta-Agonists; D002155:Calsequestrin; D002352:Carrier Proteins; D008565:Membrane Proteins; D009124:Muscle Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C493783:Slmap protein, mouse; C070048:triadin; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D002118:Calcium