title: Cooperative attachment of cross bridges predicts regulation of smooth muscle force by myosin phosphorylation.
abstract: Serine 19 phosphorylation of the myosin regulatory light chain (MRLC) appears to be the primary determinant of smooth muscle force development. The relationship between MRLC phosphorylation and force is nonlinear, showing that phosphorylation is not a simple switch regulating the number of cycling cross bridges. We reexamined the MRLC phosphorylation-force relationship in slow, tonic swine carotid media; fast, phasic rabbit urinary bladder detrusor; and very fast, tonic rat anococcygeus. We found a sigmoidal dependence of force on MRLC phosphorylation in all three tissues with a threshold for force development of approximately 0.15 mol P(i)/mol MRLC. This behavior suggests that force is regulated in a highly cooperative manner. We then determined whether a model that employs both the latch-bridge hypothesis and cooperative activation could reproduce the relationship between Ser(19)-MRLC phosphorylation and force without the need for a second regulatory system. We based this model on skeletal muscle in which attached cross bridges cooperatively activate thin filaments to facilitate cross-bridge attachment. We found that such a model describes both the steady-state and time-course relationship between Ser(19)-MRLC phosphorylation and force. The model required both cooperative activation and latch-bridge formation to predict force. The best fit of the model occurred when binding of a cross bridge cooperatively activated seven myosin binding sites on the thin filament. This result suggests cooperative mechanisms analogous to skeletal muscle that will require testing.
authors.affiliation: Box 801395, Cardiovascular Division, Univ. of Virginia Health System, Charlottesville, VA 22908-1395, USA. crembold@virginia.edu
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rembold
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wardle
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wingard
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Batts
authors.forename: Elaine F
authors.initials: EF
authors.lastname: Etter
authors.forename: Richard A
authors.initials: RA
authors.lastname: Murphy
mesh_terms: D000818:Animals; D005260:Female; D008297:Male; D008954:Models, Biological; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D018994:Myosin Light Chains / Q000502:physiology; D010766:Phosphorylation; D011817:Rabbits; D051381:Rats; D024745:Smooth Muscle Myosins / Q000502:physiology*; D013552:Swine
chemical_list: D018994:Myosin Light Chains; D024745:Smooth Muscle Myosins