Regulation of contraction in striated muscle

Regulation of Contraction in Striated Muscle. Physiol. Rev. 80: 853-924, 20 00 -Ca2+ regulation of contraction in vertebrate striated:muscle is exerted primarily through effects on the thin filament, which regulate strong cros s-bridge binding to actin. Structural and biochemical studies suggest that the position of tropomyosin (Tm) and troponin (Tn) on the thin filament det ermines the interaction of myosin with the binding sites on actin. These bi nding sites can be characterized as blocked (unable to bind to cross bridge s), closed (able to weakly bind cross bridges), or open (able to bind cross bridges so that they subsequently isomerize to become strongly bound and r elease ATP hydrolysis products). Flexibility of the Tn may allow variabilit y in actin (A) affinity for myosin along the thin filament other than throu gh a single 7 actin: 1 tropomyosin:1 tropofiin (A(7)TmTn) regulatory unit. Tm position on the actin filament is regulated by the occupancy of NH-terrn inal Ca2+ binding sites on TnC, conformational changes resulting from Ca2binding, and changes in the interactions among Tn, Tm, and actin and as wel l as by strong SI binding to actin. Ca2+ binding: to TnC enhances TnC-TnI i nteraction, weakens TnI attachment to its binding sites on 1-2 actins of th e regulatory unit, increases Tm movement over the actin surface, and expose s myosin-binding sites on actin previously blocked by Tm. Adjacent Tm are c oupled in their overlap regions where Tm movement is also controlled by int eractions with TnT. TnT also interacts with TnC-TnI in a Ca2+-dependent man ner. All these interactions may vary with the different protein isoforms. T he movement of Tm over the actin surface increases the "open" probability o f myosin binding sites on actins so that some are in the open configuration available for myosin binding and cross-bridge isomerization to strong bind ing, force-producing states. In skeletal muscle, strong binding of cycling cross bridges promotes additional Tm movement. This movement effectively st abilizes Tm in the open position and allows cooperative activation of addit ional actins in that and possibly neighboring A(7)TmTn regulatory units. Th e structural and biochemical findings support the physiological observation s of steady-state and transient mechanical behavior. Physiological studies suggest the following. 1) Ca2+ binding to Tn/Tm exposes sites on actin to w hich myosin can bind.,2) Ca2+ regulates the strong binding of M . ADP . P-i to actin, which precedes the production of force (and/or shortening) and r elease of hydrolysis products. 3) The initial rate of force development dep ends mostly on the extent of Ca2+ activation of the thin filament and myosi n kinetic properties but depends little on the initial force level. 4) A sm all number of strongly attached cross bridges within an A(7)TmTn regulatory unit can activate the actins in one unit and perhaps those in neighboring units. This results in additional myosin binding and isomerization to stron gly bound states and force production. 5) The rates of the product. release steps per se (as indicated by the unloaded shortening velocity) early in s hortening are largely independent of the extent of thin filament activation ([Ca2+]) beyond a given baseline level. However, with a greaterextent of s hortening, the rates depend on the activation level. 6) The cooperativity b etween neighboring regulatory units contributes to the activation by strong cross bridges of steady-state force but does not affect the rate of force development. 7) Strongly attached, cycling cross bridges can delay relaxation in skeleta l muscle in a cooperative manner. 8) Strongly attached and cycling cross br idges can enhance Ca2+ binding to cardiac TnC, but influence skeletal TnC t o a lesser extent. 9) Different Tn subunit isoforms can modulate the cross- bridge detachment rate as shown by studies with mutant regulatory proteins in myotubes and in In vitro motility assays. These results and conclusions suggest possible explanations for differences between skeletal and cardiac muscle regulation and delineate the paths future research may take toward a better understanding of striated muscle regulation.