This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ?-adrenergic modulation of cardiac contractility occurs, in part, through protein kinase A (PKA) myofibrillar protein phosphorylation. PKA targets the N-terminus of cardiac troponin I (cTnI), cardiac myosin-binding protein C (cMyBP-C) and titin. To isolate the effects of cTnI phosphorylation from cMyBP-C/titin phosphorylation on force-[Ca2+] relations, endogenous cardiac troponin (cTn) in rat skinned trabeculae was passively exchanged with either WT cTn, cTn containing a non-phosphorylatable cTnI(S23/24A) mutant, or a phosphomimetic cTnI(S23/24D) mutant. PKA cannot phosphorylate either cTnI mutant, thus leaving MyBP-C and titin as the sole PKA targets in those preparations. Force-[Ca2+] relationships and Ca2+-sensitivity (pCa50) were measured at 2.3 and 2.0 ?m SL. pCa50 was similar between WT Tn and Tn containing cTnI(S23/24A) trabeculae at both long and short SL, with decreased pCa50 at short SL. PKA treatment of WT and cTnI(S23,24A) exchanged trabeculae reduced pCa50 at both SL, but to a greater extent 2.3 um SL, eliminating the SL-dependence of pCa50 for both conditions. Exchange with cTn containing cTnI(S23/24D) reduced pCa50 at both SL (compared to WT and cTnI(S23,24A)) and also eliminated the influence of SL on pCa50. In summary, phosphorylation of cTnI and cardiac C-protein/titin both independently reduced pCa50, but to greater extents at longer SLs, thus reducing length dependence of Ca2+ sensitivity of force. In order to get insight into why this is so, small-angle x-ray diffraction was performed to determine whether these shifts in pCa50 were associated with changes in myofilament spacing or interaction.
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