Interaction of cardiac troponin with cardiotonic drugs: A structural perspective

Abstract

Over the forty years since its discovery, many studies have focused on understanding the role of troponin as a myofilament based molecular switch in regulating the Ca 2+ -dependent activation of striated muscle contraction. Recently, studies have explored the role of cardiac troponin as a target for cardiotonic agents. These drugs are clinically useful for treating heart failure, a condition in which the heart is no longer able to pump enough blood to other organs. These agents act via a mechanism that modulates the Ca 2+ -sensitivity of troponin; such a mode of action is therapeutically desirable because intracellular Ca 2+ concentration is not perturbed, preserving the regulation of other Ca 2+ -based signaling pathways. This review describes molecular details of the interaction of cardiac troponin with a variety of cardiotonic drugs. We present recent structural work that has identified the docking sites of several cardiotonic drugs in the troponin C -troponin I interface and discuss their relevance in the design of troponin based drugs for the treatment of heart disease.

Investigating the role of uncoupling of troponin I phosphorylation from changes in myofibrillar Ca2+-sensitivity in the pathogenesis of cardiomyopathy

“…Of particular interest are the Ca 2+ -sensitizing drugs EMD57033 and Bepridil (Li et al, 2008). When tested in the IVMA, with thin filaments containing native human Tn, both these drugs increased Ca 2+ -sensitivity by 2–3-fold and at the same time uncoupled Ca 2+ -sensitivity from TnI phosphorylation (see Figure 4A).…”

A structural and functional perspective into the mechanism of Ca2+-sensitizers that target the cardiac troponin complex

“…In response to the negative long-term performance of these drugs, another treatment scheme being explored is to increase the Ca 2+ -sensitivity of the thin filament, and thus improve contractility without modulating Ca 2+ concentration. This class of pharmaceuticals is referred to as Ca 2+ -sensitizers [4–6]. Levosimendan is a positive inotrope that binds cTnC to elicit its Ca 2+ -sensitizing function [7–9].…”

Solution Structure of Human Cardiac Troponin C in Complex with the Green Tea Polyphenol, (−)-Epigallocatechin 3-Gallate

“…For recent reviews on the molecular mechanism of these compounds and others see Refs. [17][18][19]. The discovery of small molecules that bind to cCTnC to elicit their Ca 2ϩ -sensitizing effects suggests that cCTnC is also a suitable target for the development of therapeutics.…”