DOI: 10.5176/2382-607X_ARP14.27
Authors: Brandon J. Biesiadecki
Abstract: The troponin complex is a critical thin filament molecular switch involved in transducing the calcium signal into contraction. Troponin I (TnI), the inhibitory subunit of the troponin complex, is phosphorylated as a key regulatory mechanism to directly alter the calcium regulation of cardiac contraction. TnI can undergo phosphorylation at a number of residues, however in the normal heart about 40{6e6090cdd558c53a8bc18225ef4499fead9160abd3419ad4f137e902b483c465} of TnI is basally phosphorylated at Ser-23 and 24 (pTnI S23/24) with its modulation invoking significant contractile effects. Together with other groups, our laboratory has demonstrated the effects of pTnI S23/24 are dependent upon its integrated myofilament background. It is likely that any additional TnI phosphorylation will occur on a TnI molecule already containing pTnI S23/24. To understand the significance of multiple, integrated TnI phosphorylations on the regulation of cardiac contraction we identified and investigated TnI phosphorylation combinations relevant to pathologic stress. In response to myocardial ischemia we observed phosphorylation of both TnI S23/24 and Ser-150. Similar to previous findings, pTnI S23/24 in isolation decreased calcium sensitive force production and accelerated thin filament deactivation. In contrast, isolated TnI Ser-150 phosphorylation increased calcium sensitivity and slowed filament deactivation, however, its integration with pTnI S23/24 resulted in normal calcium sensitivity while maintaining accelerated filament deactivation. These data demonstrate the modulatory outcome of a given TnI phosphorylation can be different dependent upon whether it occurs in isolation or in combination. Understanding the modulatory effects of multiple stress induced TnI phopshorylations on cardiac contractile regulation is therefore not as simple as understanding these phosphorylations in isolation, but rather we must consider their effects in the integrated context that they occur.
Keywords: troponin, troponin I, phosphorylation, calcium sensitivity
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