Effects of actin-myosin kinetics on the calcium sensitivity of regulated thin filaments.
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.
Sich
Nicholas M
NM
Department of Biochemistry, University of Nevada School of Medicine, Reno, Nevada 89557, USA.
O'Donnell
Timothy J
TJ
Coulter
Sarah A
SA
John
Olivia A
OA
Carter
Michael S
MS
Cremo
Christine R
CR
Baker
Josh E
JE
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
D000199:Actins; D006576:Heterocyclic Compounds, 4 or More Rings; D014335:Tropomyosin; D014336:Troponin; C472645:blebbistatin; D009218:Myosins; D002118:Calcium