Structure, function, and regulation of troponin C.

O ur understanding of the critical role of Ca2' in muscle function dates back to Ringer's landmark observation in 1883 that Ca2' is required for the maintenance of the contractile state in frog myocardium.1 Almost 60 years later, the pioneering work of Heilbrunn23 first suggested that Ca2+ might serve as the intracellular trigger for contractility. This idea remained controversial until 1967, when Ebashi and coworkers4 identified troponin as the Ca2+ binding site of the thin filament. Subsequent work by Greaser and Gergely5 showed that troponin comprises three protein subunits and that one of these, troponin C (TnC), binds calcium and is responsible for regulating the process of thin filament activation during skeletal muscle contraction. During the past 25 years, a large body of research has helped to further define the roles of Ca24 and TnC in controlling thin filament activation in cardiac and skeletal muscle. Most of these studies have used classic protein biochemistry in conjunction with biophysical techniques in an attempt to elucidate the structure of TnC and the mechanisms by which Ca24 binding to TnC facilitates contractility. Although this work has greatly expanded our knowledge of the biochemical bases of contractility, the recent cloning of the TnC complementary DNAs (cDNAs) and genes has made it possible, for the first time, to apply powerful molecular biological methods to studies of TnC structure, function, and regulation. The purpose of this review is to summarize the current state of knowledge concerning the structure, function, and regulation of the TnC genes and proteins. This is not intended to be an exhaustive review of TnC biology and biochemistry but rather a critical overview of this field with particular emphasis on previous contributions and the future potential of molecular biology. (Given the large volume of prior research in this area,