Effects of Cardiac Troponin I Mutation P83S on Contractile Properties and the Modulation by PKA-Mediated Phosphorylation
2016
Cheng, Yuanhua | Lindert, Steffen | Oxenford, Lucas | Tu, An-yue | McCulloch, Andrew D. | Regnier, Michael
cTnIᴾ⁸²S (cTnIᴾ⁸³S in rodents) resides at the I-T arm of cardiac troponin I (cTnI) and was initially identified as a disease-causing mutation of hypertrophic cardiomyopathy (HCM). However, later studies suggested this may not be true. We recently reported that introduction of an HCM-associated mutation in either inhibitory-peptide (cTnIᴿ¹⁴⁶ᴳ) or cardiac-specific N-terminus (cTnIᴿ²¹C) of cTnI blunts the PKA-mediated modulation on myofibril activation/relaxation kinetics by prohibiting formation of intrasubunit contacts between these regions. Here, we tested whether this also occurs for cTnIᴾ⁸³S. cTnIᴾ⁸³S increased both Ca²⁺ binding affinity to cTn (KCₐ) and affinity of cTnC for cTnI (KC–I), and eliminated the reduction of KCₐ and KC–I observed for phosphorylated-cTnIᵂᵀ. In isolated myofibrils, cTnIᴾ⁸³S maintained maximal tension (TMAX) and Ca²⁺ sensitivity of tension (pCa₅₀). For cTnIᵂᵀ myofibrils, PKA-mediated phosphorylation decreased pCa₅₀ and sped up the slow-phase relaxation (especially for those Ca²⁺ conditions that heart performs in vivo). Those effects were blunted for cTnIᴾ⁸³S myofibrils. Molecular-dynamics simulations suggested cTnIᴾ⁸³S moderately inhibited an intrasubunit interaction formation between inhibitory-peptide and N-terminus, but this “blunting” effect was weaker than that with cTnIᴿ¹⁴⁶ᴳ or cTnIᴿ²¹C. In summary, cTnIᴾ⁸³S has similar effects as other HCM-associated cTnI mutations on troponin and myofibril function even though it is in the I-T arm of cTnI.
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