TY - JOUR
T1 - Force development and intracellular Ca2+ in intact cardiac muscles from gravin mutant mice
AU - Li, Zhitao
AU - Singh, Sonal
AU - Suryavanshi, Santosh V.
AU - Ding, Wengang
AU - Shen, Xiaoxu
AU - Wijaya, Cori S.
AU - Gao, Wei Dong
AU - McConnell, Bradley K.
N1 - Funding Information:
The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) under Award Number R01HL085487 (to B.K.M.) and R15HL124458 (to B.K.M.) supported research reported in this publication. Research was also supported by an American Heart Association (AHA) grant under Award Number 0855439E (to W.D.G). The content is solely the responsibility of the authors, and does not necessarily represent the official views of the NIH or AHA.
Publisher Copyright:
© 2017 Elsevier B.V.
PY - 2017
Y1 - 2017
N2 - Gravin (AKAP12) is an A-kinase-anchoring-protein that scaffolds protein kinase A (PKA), β2-adrenergic receptor (β2-AR), protein phosphatase 2B and protein kinase C. Gravin facilitates β2-AR-dependent signal transduction through PKA to modulate cardiac excitation-contraction coupling and its removal positively affects cardiac contraction. Trabeculae from the right ventricles of gravin mutant (gravin-t/t) mice were employed for force determination. Simultaneously, corresponding intracellular Ca2+ transient ([Ca2+]i) were measured. Twitch force (Tf)-interval relationship, [Ca2+]i-interval relationship, and the rate of decay of post-extrasysolic potentiation (Rf) were also obtained. Western blot analysis were performed to correlate sarcomeric protein expression with alterations in calcium cycling between the WT and gravin-t/t hearts. Gravin-t/t muscles had similar developed force compared to WT muscles despite having lower [Ca2+]i at any given external Ca2+ concentration ([Ca2+]o). The time to peak force and peak [Ca2+]i were slower and the time to 75% relaxation was significantly prolonged in gravin-t/t muscles. Both Tf-interval and [Ca2+]i-interval relations were depressed in gravin-t/t muscles. Rf, however, did not change. Furthermore, Western blot analysis revealed decreased ryanodine receptor (RyR2) phosphorylation in gravin-t/t hearts. Gravin-t/t cardiac muscle exhibits increased force development in responsiveness to Ca2+. The Ca2+ cycling across the SR appears to be unaltered in gravin-t/t muscle. Our study suggests that gravin is an important component of cardiac contraction regulation via increasing myofilament sensitivity to calcium. Further elucidation of the mechanism can provide insights to role of gravin if any in the pathophysiology of impaired contractility.
AB - Gravin (AKAP12) is an A-kinase-anchoring-protein that scaffolds protein kinase A (PKA), β2-adrenergic receptor (β2-AR), protein phosphatase 2B and protein kinase C. Gravin facilitates β2-AR-dependent signal transduction through PKA to modulate cardiac excitation-contraction coupling and its removal positively affects cardiac contraction. Trabeculae from the right ventricles of gravin mutant (gravin-t/t) mice were employed for force determination. Simultaneously, corresponding intracellular Ca2+ transient ([Ca2+]i) were measured. Twitch force (Tf)-interval relationship, [Ca2+]i-interval relationship, and the rate of decay of post-extrasysolic potentiation (Rf) were also obtained. Western blot analysis were performed to correlate sarcomeric protein expression with alterations in calcium cycling between the WT and gravin-t/t hearts. Gravin-t/t muscles had similar developed force compared to WT muscles despite having lower [Ca2+]i at any given external Ca2+ concentration ([Ca2+]o). The time to peak force and peak [Ca2+]i were slower and the time to 75% relaxation was significantly prolonged in gravin-t/t muscles. Both Tf-interval and [Ca2+]i-interval relations were depressed in gravin-t/t muscles. Rf, however, did not change. Furthermore, Western blot analysis revealed decreased ryanodine receptor (RyR2) phosphorylation in gravin-t/t hearts. Gravin-t/t cardiac muscle exhibits increased force development in responsiveness to Ca2+. The Ca2+ cycling across the SR appears to be unaltered in gravin-t/t muscle. Our study suggests that gravin is an important component of cardiac contraction regulation via increasing myofilament sensitivity to calcium. Further elucidation of the mechanism can provide insights to role of gravin if any in the pathophysiology of impaired contractility.
KW - Cardiac muscle
KW - Contraction
KW - Force development
KW - Gravin
KW - Intracellular calcium
KW - Trabeculae
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U2 - 10.1016/j.ejphar.2017.04.020
DO - 10.1016/j.ejphar.2017.04.020
M3 - Article
C2 - 28428008
AN - SCOPUS:85017540518
SN - 0014-2999
VL - 807
SP - 117
EP - 126
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
ER -