The unique functions of cardiac troponin I in the control of cardiac muscle contraction and relaxation

Abstract

We review development of evidence and current perceptions of the multiple and significant functions of cardiac troponin I in regulation and modulation of cardiac function. Our emphasis is on the unique structure function relations of the cardiac isoform of troponin I, especially regions containing sites of phosphorylation. The data indicate that modifications of specific regions cardiac troponin I by phosphorylations either promote or reduce cardiac contractility. Thus, a homeostatic balance in these phosphorylations is an important aspect of control of cardiac function. A new concept is the idea that the homeostatic mechanisms may involve modifications of intra-molecular interactions in cardiac troponin I. KeywordsCardiac; Sarcomeres; Adrenergic stimulation; Mechanics; Kinases; Phosphatases In the time since the troponin discovery and naming by the laboratory of Setsuro Ebashi [1], there has been a constant stream of evidence indicating the substantial role of modifications in cardiac troponin (cTn) as a critical control element in the body's response to physiological stressors such as the hemodynamic demands of exercise. It is now widely recognized that regulatory processes at the level of the sarcomeres and the hetero-trimeric Tn complex involve not only the reception of Ca 2+ by cTnC, but also transduction of this Ca-binding signal by cTnI and cTnT [2,3]. Multiple interactions of cTnI and cTnT with actin and tropomyosin (Tm) control the number and kinetics of interactions of cross-bridges with the thin filament. Our focus here on cTnI serves to highlight the significant impact of modifications in the function of Tn in working cardiac myocytes and in the integrated physiological responses to exercise, which we have reviewed previously [4,5]. Evidence summarized below indicates that phosphorylation of cTnI by adrenergic signaling cascades is an indispensable control mechanism in matching cardiac output to venous return and myocyte dynamics to heart rate. Specific modifications in troponin I affect the dynamics and intensity of the heart beatElucidation of the function of an N-terminal extension of ~30 amino acids with sites (Ser-23, Ser-24) of phosphorylation by protein kinase A (PKA), not present in the fast skeletal (fsTnI) or slow skeletal isoforms (ssTnI), provided the first evidence that cTnI may have a special role * Corresponding

A preferred AMPK phosphorylation site adjacent to the inhibitory loop of cardiac and skeletal troponin I

“…7). Ser149, a highly conserved residue in TnI, is located adjacent to the inhibitory loop, a segment spanning amino acids 136-147 (human sequence excluding the initial methionine) that has been shown to be the minimum sequence of cTnI that prevents actomyosin ATPase activity in the absence of Ca 2þ -bound cTnC [46][47][48] and therefore, key for the inhibitory properties of TnI. Ser149 is also located adjacent to the switch region (amino acids 150-159), an amphiphilic a-helix that binds a hydrophobic cleft on TnC and is thought to act as a Ca 2þ transducer, signaling the binding of Ca 2þ to TnC to the rest of the contractile apparatus.…”

“…Ser149 is also located adjacent to the switch region (amino acids 150-159), an amphiphilic a-helix that binds a hydrophobic cleft on TnC and is thought to act as a Ca 2þ transducer, signaling the binding of Ca 2þ to TnC to the rest of the contractile apparatus. [46][47][48] Therefore, Ser149 is strategically positioned to possibly influence the inhibitory properties of TnI toward actin-myosin interactions and the affinity of TnI for TnC.…”

Recurrent and founder mutations in the Netherlands: cardiac Troponin I (TNNI3) gene mutations as a cause of severe forms of hypertrophic and restrictive cardiomyopathy*

“…Almost all affected carriers in our study and those known from literature [11] have obstructive HCM (in some cases myectomy was performed) including asymmetrical septum hypertrophy and ECG abnormalities. The mutation affects a PKA phosphorylation site [12] and phosphorylation of this site influences the interaction of troponin I with the calcium-binding site of troponin C [9]. HCM-causing missense mutations within the amphipathic alpha-helix of TNNI3, spanning amino acids 164 to 188 and probably involved in the binding to actintropomyosin, cause an increased calcium sensitivity while DCM-causing mutations cause a decreased sensitivity [7].…”

“…1). The positions of reported mutations in TNNI3 reveal the presence of important functional domains, such as protein binding or regulatory domains [9], such as phosphorylation sites in the N-terminal part of cardiac troponin [10].…”

Cardiac thin filament regulation

“…For a detailed description of the structure/domain organization of cTnI, the reader is referred to a recent overview [70]. There are at least two actin-interacting sites along TnI sequence: the inhibitory region and a second actin-Tm binding site.…”