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.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Biotechnology Resource Grants (P41)
Project #
5P41RR008630-16
Application #
8361296
Study Section
Special Emphasis Panel (ZRG1-BCMB-E (40))
Project Start
2011-01-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
16
Fiscal Year
2011
Total Cost
$19,716
Indirect Cost
Name
Illinois Institute of Technology
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
042084434
City
Chicago
State
IL
Country
United States
Zip Code
60616
Yazdi, Aliakbar Khalili; Vezina, Grant C; Shilton, Brian H (2017) An alternate mode of oligomerization for E. coli SecA. Sci Rep 7:11747
Sullivan, Brendan; Robison, Gregory; Pushkar, Yulia et al. (2017) Copper accumulation in rodent brain astrocytes: A species difference. J Trace Elem Med Biol 39:6-13
Morris, Martha Clare (2016) Nutrition and risk of dementia: overview and methodological issues. Ann N Y Acad Sci 1367:31-7
Robison, Gregory; Sullivan, Brendan; Cannon, Jason R et al. (2015) Identification of dopaminergic neurons of the substantia nigra pars compacta as a target of manganese accumulation. Metallomics 7:748-55
Gelfand, Paul; Smith, Randy J; Stavitski, Eli et al. (2015) Characterization of Protein Structural Changes in Living Cells Using Time-Lapsed FTIR Imaging. Anal Chem 87:6025-31
Liang, Wenguang G; Ren, Min; Zhao, Fan et al. (2015) Structures of human CCL18, CCL3, and CCL4 reveal molecular determinants for quaternary structures and sensitivity to insulin-degrading enzyme. J Mol Biol 427:1345-1358
Zhou, Hao; Li, Shangyang; Badger, John et al. (2015) Modulation of HIV protease flexibility by the T80N mutation. Proteins 83:1929-39
Nobrega, R Paul; Arora, Karunesh; Kathuria, Sagar V et al. (2014) Modulation of frustration in folding by sequence permutation. Proc Natl Acad Sci U S A 111:10562-7
Jiao, Lianying; Ouyang, Songying; Shaw, Neil et al. (2014) Mechanism of the Rpn13-induced activation of Uch37. Protein Cell 5:616-30
Witayavanitkul, Namthip; Ait Mou, Younss; Kuster, Diederik W D et al. (2014) Myocardial infarction-induced N-terminal fragment of cardiac myosin-binding protein C (cMyBP-C) impairs myofilament function in human myocardium. J Biol Chem 289:8818-27

Showing the most recent 10 out of 96 publications