title: The myosin-activated thin filament regulatory state, M⁻-open: a link to hypertrophic cardiomyopathy (HCM).
abstract: This review proposes a link between the hypertrophic (HCM) and restrictive cardiomyopathies caused by mutations in several sarcomeric thin filament proteins, and the open state of the three-state muscle regulation theory. The three characteristics of various muscle systems reconstituted from HCM mutated proteins (increased Ca(2+)-sensitivity, increased basal activity in the absence of Ca(2+), and decreased cooperativity) can be explained by the contribution of a myosin-induced open state (M (-) ), which elevates the basal activity and competes with the normal Ca(2+)-activated pathway. A model based on the three-state theory of regulation, shows how a change in the closed/blocked equilibrium caused by a mutation that weakens the binding of troponin I to tropomyosin-actin can produce the characteristics of HCM. This review also shows that in the M (-) state, Ca(2+) can shift the closed-open equilibrium of the N-terminal hydrophobic region of troponin C without affecting activity.
authors.affiliation: , 4416 Great Meadow Rd, Dedham, MA, USA, Sherwin.lehrer@gmail.com.
authors.forename: Sherwin S
authors.initials: SS
authors.lastname: Lehrer
authors.forename: Michael A
authors.initials: MA
authors.lastname: Geeves
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000378:metabolism*; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D014335:Tropomyosin / Q000378:metabolism*; D014336:Troponin / Q000378:metabolism*
chemical_list: D014335:Tropomyosin; D014336:Troponin; D009218:Myosins; D002118:Calcium
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