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- W2062508731 abstract "Protein kinase A (PKA) phosphorylation of myofibrillar proteins constitutes an important pathway for beta-adrenergic modulation of cardiac contractility and relaxation. PKA targets the N-terminus of cardiac troponin I (cTnI), cardiac myosin-binding protein C (cMyBP-C) and titin. We recently reported that PKA phosphorylation of cTnI alone, or in combination with cMyBP-C, is sufficient to suppress cardiac contractility and the sarcomere length dependence of contraction. Troponin C (cTnC) interaction with cTnI (C-I) is a critical step in contractile activation that may be modulated by cTnI phosphorylation. Here we tested the hypothesis that altering C-I interactions by PKA, or by phosphomimetic mutations in cTnI, directly affects myofilament relaxation. Using a fluorescent probe coupled to cTnC (C35S IANBD), the Ca2+ binding affinity to troponin complex (cTn) and C-I interaction affinity were monitored. Ca2+ binding to cTn (pCa50) was significantly decreased by PKA, when both whole cTn or cTnI alone were phosphorylated (pCa50 = 0.3 and 0.1 units, respectively). PKA phosphorylation of cTnI also weakened C-I interaction in the presence or absence of Ca2+, with a greater effect for the former. Rat ventricular myofibrils were isolated and endogenous cTn was exchanged with either wild type (WT), nonphosphorylatable (S23/24A cTnI) or phosphomimetic (S23/24D cTnI) recombinant cTn. Mechanics were monitored at maximum and submaximal Ca2+. PKA treatment of WT or S23/24D cTnI exchange resulted in a significantly increased slow phase relaxation rate (kREL,slow) and decreased duration of slow phase relaxation (tREL,slow). These effects were largest at submaximal Ca2+. In contrast, exchange with S23/24A cTnI resulted in no effects on relaxation kinetics. Together these data suggest that weakened C-I interaction affinity from PKA phosphorylation results in increased myofilament relaxation kinetics. These effects may enhance early phase diastolic relaxation during beta-adrenergic stimulation. Supported by AHA7400069 (VR), AHA2090056 (DW), HL65497 (MR)." @default.
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- W2062508731 date "2013-01-01" @default.
- W2062508731 modified "2023-09-29" @default.
- W2062508731 title "PKA Effects on Cardiac Troponin and Myofibril Relaxation" @default.
- W2062508731 doi "https://doi.org/10.1016/j.bpj.2012.11.874" @default.
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