Cardiac troponin I tyrosine 26 phosphorylation decreases myofilament Ca sensitivity and accelerates deactivation Journal Article

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Authors: Salhi, H. E.; Walton, S. D.; Hassel, N. C.; Brundage, E. A.; de Tombe, P. P.; Janssen, P. M.; Davis, J. P.; Biesiadecki, B. J.
Article Title: Cardiac troponin I tyrosine 26 phosphorylation decreases myofilament Ca sensitivity and accelerates deactivation
Abstract: Troponin I (TnI), the inhibitory subunit of the troponin complex, can be phosphorylated as a key regulatory mechanism to alter the calcium regulation of contraction. Recent work has identified phosphorylation of TnI Tyr-26 in the human heart with unknown functional effects. We hypothesized that TnI Tyr-26N-terminal phosphorylation decreases calcium sensitivity of the thin filament, similar to the desensitizing effects of TnI Ser-23/24 phosphorylation. Our results demonstrate that Tyr-26 phosphorylation and pseudo-phosphorylation decrease calcium binding to troponin C (TnC) on the thin filament and calcium sensitivity of force development to a similar magnitude as TnI Ser-23/24 pseudo-phosphorylation. To investigate the effects of TnI Tyr-26 phosphorylation on myofilament deactivation, we measured the rate of calcium dissociation from TnC. Results demonstrate that filaments containing Tyr-26 pseudo-phosphorylated TnI accelerate the rate of calcium dissociation from TnC similar to that of TnI Ser-23/24. Finally, to assess functional integration of TnI Tyr-26 with Ser-23/24 phosphorylation, we generated recombinant TnI phospho-mimetic substitutions at all three residues. Our biochemical analyses demonstrated no additive effect on calcium sensitivity or calcium-sensitive force development imposed by Tyr-26 and Ser-23/24 phosphorylation integration. However, integration of Tyr-26 phosphorylation with pseudo-phosphorylated Ser-23/24 further accelerated thin filament deactivation. Our findings suggest that TnI Tyr-26 phosphorylation functions similarly to Ser-23/24N-terminal phosphorylation to decrease myofilament calcium sensitivity and accelerate myofilament relaxation. Furthermore, Tyr-26 phosphorylation can buffer the desensitization of Ser-23/24 phosphorylation while further accelerating thin filament deactivation. Therefore, the functional integration of TnI phosphorylation may be a common mechanism to modulate Ser-23/24 phosphorylation function.
Journal Title: Journal of Molecular and Cellular Cardiology
Volume: 76C
ISSN: 1095-8584; 0022-2828
Publisher: Unknown  
Date Published: 2014
Start Page: 257
End Page: 264
Language: ENG
DOI/URL:

S0022-2828(14)00294-6
Notes: LR: 20141022; CI: Copyright (c) 2014; GR: R01 HL114940/HL/NHLBI NIH HHS/United States; JID: 0262322; OTO: NOTNLM; 2014/07/07 [received]; 2014/09/09 [revised]; 2014/09/12 [accepted]; aheadofprint