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Differential roles of regulatory light chain and myosin binding protein‐C phosphorylations in the modulation of cardiac force development
Author(s) -
Colson Brett A.,
Locher Matthew R.,
Bekyarova Tanya,
Patel Jitandrakumar R.,
Fitzsimons Daniel P.,
Irving Thomas C.,
Moss Richard L.
Publication year - 2010
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.183897
Subject(s) - myosin light chain kinase , phosphorylation , myosin , biophysics , chemistry , actin , protein kinase a , immunoglobulin light chain , biochemistry , biology , antibody , immunology
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 Ca 2+ 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 Ca 2+ ‐independent force and maximum Ca 2+ ‐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 1,1 / I 1,0 ) 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 1,1 / I 1,0 and, as hypothesized, treatment with MLCK also increased I 1,1 / I 1,0 , which can explain the accelerated rates of force development during activation. Importantly, interfilament spacing was reduced by ∼2 nm (Δ 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 Ca 2+ sensitivity of force is mediated by a distinct mechanism, most probably involving changes in interfilament spacing.