期刊
JOURNAL OF PHYSIOLOGY-LONDON
卷 588, 期 6, 页码 981-993出版社
WILEY
DOI: 10.1113/jphysiol.2009.183897
关键词
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资金
- American Heart Association
- NIH [HL-R37-82900, RR-08630]
- US DOE, Basic Energy Sciences, Office of Science [W-31-109-ENG-38]
Phosphorylation of myosin regulatory light chain (RLC) by myosin light chain kinase (MLCK) and myosin binding protein-C (cMyBP-C) by protein kinase A (PKA) independently accelerate the kinetics of force development in ventricular myocardium. However, while MLCK treatment has been shown to increase the Ca2+ sensitivity of force (pCa(50)), PKA treatment has been shown to decrease pCa(50), presumably due to cardiac troponin I phosphorylation. Further, MLCK treatment increases Ca2+-independent force and maximum Ca2+-activated force, whereas PKA treatment has no effect on either force. To investigate the structural basis underlying the kinase-specific differential effects on steady-state force, we used synchrotron low-angle X-ray diffraction to compare equatorial intensity ratios (I-1,I-1/I-1,I-0) to assess the proximity of myosin cross-bridge mass relative to actin and to compare lattice spacings (d(1,0)) to assess the inter-thick filament spacing in skinned myocardium following treatment with either MLCK or PKA. As we showed previously, PKA phosphorylation of cMyBP-C increases I-1,I-1/I-1,I-0 and, as hypothesized, treatment with MLCK also increased I-1,I-1/I-1,I-0, which can explain the accelerated rates of force development during activation. Importantly, interfilament spacing was reduced by similar to 2 nm (delta 3.5%) with MLCK treatment, but did not change with PKA treatment. Thus, RLC or cMyBP-C phosphorylation increases the proximity of cross-bridges to actin, but only RLC phosphorylation affects lattice spacing, which suggests that RLC and cMyBP-C modulate the kinetics of force development by similar structural mechanisms; however, the effect of RLC phosphorylation to increase the Ca2+ sensitivity of force is mediated by a distinct mechanism, most probably involving changes in interfilament spacing.
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