Biophysics Seminar - 04/09/2008 - 2:30pm - 1080 Physics Research Building

Molecular Determinants of Cardiac and Skeletal Muscle Relaxation: the Merging of Biochemistry and Physiology
Jonathan Davis, Department of Physiology and Cell Biology

At the molecular level, there are three general processes that potentially play a pivotal role in setting the rate of striated (skeletal and cardiac) muscle relaxation: 1) the rate of decline in the Ca²⁺ transient; 2) the rate of myosin detachment from actin and 3) the rate of Ca²⁺ dissociation from troponin C (TnC). It is generally thought that either the Ca²⁺ transient or myosin control the rate-limiting step of striated muscle relaxation since the rate of Ca²⁺ dissociation from isolated TnC is an order of magnitude faster than the rate of muscle relaxation. However, TnC does not function in muscle in isolation, but as part of a troponin complex (consisting of troponin C, I and T) that is anchored to the thin filament through multiple contacts with tropomyosin and actin. Thus, the Ca²⁺ binding properties of isolated TnC may be a poor model system for TnC behavior in muscle. To address this possibility, the rates of Ca²⁺ dissociation from TnC were measured using fluorescence stopped-flow technology in systems of increasing complexity from isolated TnC to various troponin complexes to reconstituted thin filaments (actin:tropomyosin:troponin ± myosin S1) and finally in rigor myofibrils (small muscle pieces). Both thin and thick filament proteins influence the ability of TnC to sense and respond to a Ca²⁺ signal. Furthermore, in the presence of strongly bound myosin (utilizing reconstituted thin filaments or myofibrils), the rates of Ca²⁺ dissociation from cardiac and skeletal TnC were observed to be similar to the rates of muscle relaxation. Thus, the concept of a single molecular event being the all-inclusive rate-limiting step for striated muscle relaxation is an oversimplification. Supported by awards from the NIH and AHA.