title: Effects of actin-myosin kinetics on the calcium sensitivity of regulated thin filaments.
abstract: Activation of thin filaments in striated muscle occurs when tropomyosin exposes myosin binding sites on actin either through calcium-troponin (Ca-Tn) binding or by actin-myosin (A-M) strong binding. However, the extent to which these binding events contributes to thin filament activation remains unclear. Here we propose a simple analytical model in which strong A-M binding and Ca-Tn binding independently activates the rate of A-M weak-to-strong binding. The model predicts how the level of activation varies with pCa as well as A-M attachment, N·k(att), and detachment, k(det), kinetics. To test the model, we use an in vitro motility assay to measure the myosin-based sliding velocities of thin filaments at different pCa, N·k(att), and k(det) values. We observe that the combined effects of varying pCa, N·k(att), and k(det) are accurately fit by the analytical model. The model and supporting data imply that changes in attachment and detachment kinetics predictably affect the calcium sensitivity of striated muscle mechanics, providing a novel A-M kinetic-based interpretation for perturbations (e.g. disease-related mutations) that alter calcium sensitivity.
authors.affiliation: Department of Biochemistry, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Sich
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: O'Donnell
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Coulter
authors.forename: Olivia A
authors.initials: OA
authors.lastname: John
authors.forename: Michael S
authors.initials: MS
authors.lastname: Carter
authors.forename: Christine R
authors.initials: CR
authors.lastname: Cremo
authors.forename: Josh E
authors.initials: JE
authors.lastname: Baker
mesh_terms: D008841:Actin Cytoskeleton; D000199:Actins / Q000737:chemistry*; D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry; D007700:Kinetics; D008962:Models, Theoretical; D009119:Muscle Contraction; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation; D009218:Myosins / Q000737:chemistry*; D011817:Rabbits; D014335:Tropomyosin / Q000737:chemistry; D014336:Troponin / Q000737:chemistry
chemical_list: D000199:Actins; D006576:Heterocyclic Compounds, 4 or More Rings; D014335:Tropomyosin; D014336:Troponin; C472645:blebbistatin; D009218:Myosins; D002118:Calcium