Table.

Summary of the Known and Novel Phosphorylation Sites in This Study and the Putative Effect of Altered Phosphorylation in Heart Failure

Residue	Kinase(s)	Domain Within cTnI^{20 –26}	Physiological Effect of Phosphorylation	Putative Effect of Altered Phosphorylation in HF
S4 and S5	Unknown	Acidic region of N-terminal extension and interacts with inhibitory region when S22 and S23 are phosphorylated	Unknown	May inhibit interaction of acidic region of N terminus with inhibitory region^22,25,26; speculated to have an impact similar to that of a decrease in S22 and S23 phosphorylation³
S22 and S23	PKA³ PKC (β and δ),⁴ PKD,⁵ PKG⁶	N-terminal extension; phosphorylation results in bending of hinge region and cTnI more compact; promotes acidic region at extreme N-terminus interaction with inhibitory region	Desensitizes to Ca²⁺; may accelerate cross-bridge kinetics; decreases Ca²⁺ affinity of cTnC; increases contractile power and relaxation and length-dependent activation	Inhibits lusitropic response to β-adrenergic receptor stimulation; impairs relaxation and force frequency response; may inhibit length-dependent activation (Frank-Starling law)^3,4,7,24,27
Y25	Unknown	N-terminal extension	Unknown	Putatively similar to S22,S23
S41 and S43	PKC (β and δ)	IT arm	Decreases Ca²⁺ sensitivity; slows kinetics in motility assays and stabilizes inhibition of activation of thin filament⁹; pseudophosphorylation decreases contractility and relaxation in vivo^7,28	Impairs relaxation and force frequency response^7,9,21,22,28
T50	Unknown	IT arm	Unknown	Unknown
S76^* and T77^*	Unknown	IT-arm region; interacts with cTnT	Unknown	Unknown
T142	PKC	Within inhibitory region	Conflicting evidence on effect on Ca²⁺ sensitivity; decreases cooperativity of activation⁹; pseudophosphorylation in vivo impairs relaxation²⁸	Impairs relaxation^9,28; impairs contractile force
S165^†	PKA¹⁴	Switch peptide between 2 actin-binding regions; adjacent to key residue for acidosis impact on contractile function^30–34	Unknown	Potential impact on response to acidosis and switching of binding from actin to TnC with activation^29,30; reduced proteolysis³¹
T180 and S198	Unknown	C-terminal region involved in position of troponin along tropomyosin; also location of HCM mutants	Unknown	Could affect the position of troponin along tropomyosin, effects on activation^31,35–37; reduced proteolysis³¹

PKA indicates protein kinase A; PKC, protein kinase C; PKD, protein kinase D; PKG, protein kinase G; cTnI, cardiac troponin I; cTnC, cardiac troponin C; and HCM, hypertrophic cardiomyopathy.

These sites had been noted by researchers¹⁰; however it was unclear which of the 2 sites were phosphorylated.

^†

Previously noted only in vitro.