Functional importance of the carboxyl-terminal region of striated muscle tropomyosin.
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.
Jagatheesan
Ganapathy
G
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0524, USA.
Rajan
Sudarsan
S
Petrashevskaya
Natalia
N
Schwartz
Arnold
A
Boivin
Greg
G
Vahebi
Susan
S
DeTombe
Pieter
P
Solaro
R John
RJ
Labitzke
Erin
E
Hilliard
George
G
Wieczorek
David F
DF
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
D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D014335:Tropomyosin; D020107:Troponin T; D007545:Isoproterenol