Abstract for Paper V

Dual Ca²⁺ Site Activation of Cardiac Muscle Contraction; Experimental isolation of the Ca²⁺ controls

This paper briefly reviews recent developments on the role of Ca²⁺ and Mg²⁺in myofilament activation. It then introduces the general theory of chemical cooperativity applicable to the actomyosin ATPase activity. These considerations, coupled with the observation that Ca²⁺-cooperativity is retained in an actomyosin ATPase reconstituted with short thin- filaments that contain only two troponin-tropomyosin complexes, imply that the observed cooperativity must arise from two disparate Ca²⁺ binding sites. Published data are cited that show the separation of these sites by reversible removal of the constituents responsible for control of the stimulus-contraction coupling in muscle. It is concluded that the origin of the different chemical cooperativities seen for Ca²⁺ and ATP in the activation of the ATPase are rooted in their differing participation in the separate processes of thick- and thin-filament activation both of which are required for the ATPase and force development. By comparison with data from skeletal muscle it is also shown that the thick-filament activation by Ca²⁺ is strongly implicated in the Frank–Starling Law.