title: Functional importance of the carboxyl-terminal region of striated muscle tropomyosin.
abstract: Striated muscle tropomyosin (TM) interacts with actin and the troponin complex to regulate calcium-mediated muscle contraction. Previous work by our laboratory established that alpha- and beta-TM isoforms elicit physiological differences in sarcomeric performance. Heart myofilaments containing beta-TM exhibit an increased sensitivity to calcium that is associated with a decrease in the rate of relaxation and a prolonged time of relaxation. To address whether the carboxyl-terminal, troponin T binding domain of beta-TM is responsible for these physiological alterations, we exchanged the 27 terminal amino acids of alpha-TM (amino acids 258 -284) for the corresponding region in beta-TM. Hearts of transgenic mice that express this chimeric TM protein exhibit significant decreases in their rates of contraction and relaxation when assessed by ex vivo work-performing cardiac analyses. There are increases in the time to peak pressure and a dramatic increase in end diastolic pressure. In myofilaments, this chimeric protein induces depression of maximum tension and ATPase rate, together with a significant decrease in sensitivity to calcium. Our data are the first to demonstrate that the TM isoform-specific carboxyl terminus is a critical determinant of sarcomere performance and calcium sensitivity in both the whole heart and in isolated myofilaments.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
authors.forename: Ganapathy
authors.initials: G
authors.lastname: Jagatheesan
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.forename: Natalia
authors.initials: N
authors.lastname: Petrashevskaya
authors.forename: Arnold
authors.initials: A
authors.lastname: Schwartz
authors.forename: Greg
authors.initials: G
authors.lastname: Boivin
authors.forename: Susan
authors.initials: S
authors.lastname: Vahebi
authors.forename: Pieter
authors.initials: P
authors.lastname: DeTombe
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
authors.forename: Erin
authors.initials: E
authors.lastname: Labitzke
authors.forename: George
authors.initials: G
authors.lastname: Hilliard
authors.forename: David F
authors.initials: DF
authors.lastname: Wieczorek
mesh_terms: D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure; D015180:Electrophoresis, Gel, Two-Dimensional; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006339:Heart Rate; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000502:physiology*; D009200:Myocardial Contraction; D020033:Protein Isoforms / Q000737:chemistry / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014335:Tropomyosin / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D020107:Troponin T / Q000378:metabolism
chemical_list: D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D014335:Tropomyosin; D020107:Troponin T; D007545:Isoproterenol