Interaction of cardiac troponin with cardiotonic drugs: a structural perspective.
Over the 40 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.
Li
Monica X
MX
Department of Biochemistry, University of Alberta, Edmonton, Alta., Canada.
Robertson
Ian M
IM
Sykes
Brian D
BD
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006331:Heart Diseases / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014336:Troponin / Q000737:chemistry / Q000378:metabolism*
D002316:Cardiotonic Agents; D014336:Troponin; D002118:Calcium