Biology of the troponin complex in cardiac myocytes

Troponin is the regulatory complex of the myofibrillar thin filament that plays a critical role in regulating excitation-contraction coupling in the heart. Troponin is composed of three distinct gene products: troponin C (cTnC), the 18-kD Ca2+-binding subunit; troponin I (cTnI), the ∼23-kD inhibitory subunit that prevents contraction in the absence of Ca2+ binding to cTnC; and troponin T (cTnT), the ∼35-kD subunit that attaches troponin to tropomyosin (Tm) and to the myofibrillar thin filament. Over the past 45 years, extensive biochemical, biophysical, and structural studies have helped to elucidate the molecular basis of troponin function and thin filament activation in the heart. At the onset of systole, Ca2+ binds to the N-terminal Ca2+ binding site of cTnC initiating a conformational change in cTnC, which catalyzes protein-protein associations activating the myofibrillar thin filament. Thin filament activation in turn facilitates crossbridge cycling, myofibrillar activation, and contraction of the heart. The intrinsic length-tension properties of cardiac myocytes as well as the Frank-Starling properties of the intact heart are mediated primarily through Ca2+-responsive thin filament activation. cTnC, cTnI, and cTnT are encoded by distinct single-copy genes in the human genome, each of which is expressed in a unique cardiac-restricted developmentally regulated fashion. Elucidation of the transcriptional programs that regulate troponin transcription and gene expression has provided insights into the molecular mechanisms that regulate and coordinate cardiac myocyte differentiation and provided unanticipated insights into the pathogenesis of cardiac hypertrophy. Autosomal dominant mutations in cTnI and cTnT have been identified and are associated with familial hypertrophic and restrictive cardiomyopathies. © 2004 Elsevier Inc. All rights reserved.