Key result
Expression of constitutively active Pak1 in rat cardiac myocytes significantly reduced phosphorylation of cTnI and C-protein, which was associated with an increase in sensitivity to Ca2+.
Pak1 activation in cardiac myocytes reduces phosphorylation of cTnI and C-protein, increasing calcium sensitivity and providing evidence for a novel pathway of phosphatase regulation.
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No immediate clinical implications; extends basic Pak1 signaling research in myocytes but leaves open human relevance.
We investigated intracellular localization and substrate specificity of P21-activated kinase-1 (Pak1) in rat cardiac myocytes. Pak1 is a serine/threonine protein kinase that is activated by Rac1/Cdc42 and important in signaling of stress responses. Yet the localization and in vivo function of Pak1 in heart cells is poorly understood. Studies reported here indicate that Pak1 physically interacts with protein phosphatase 2a and localizes to the Z-disk, cell membrane, intercalated disc, and nuclear membrane of adult rat heart myocytes. We compared levels of phosphorylation of cardiac troponin I (cTnI) in control myocytes with phosphorylation of cTnI and myosin binding protein C (C-protein) in myocytes with increased Pak1 activity. The increase in activity was induced by infection of myocytes with a recombinant adenovirus (AdPak1) containing cDNA for a constitutively active Pak1. Control cells were infected with a virus (AdLacZ) containing LacZ. Basal levels of phosphorylation of cTnI and C-protein were relatively high in the myocytes infected with AdLacZ. However, phosphorylation of cTnI and C-protein in cells expressing constitutively active Pak1 was significantly reduced compared with those expressing LacZ. Measurement of Ca2+ tension relations in single myocytes demonstrated that this reduction in phosphorylation of cTnI and C-protein was associated with the predicted increase in sensitivity to Ca2+. Our data provide evidence for a novel pathway of phosphatase regulation in cardiac myocytes.
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Ke et al. (2003) studied this question. Increased Pak1 activity via recombinant adenovirus (AdPak1) vs. Control cells infected with AdLacZ was evaluated on Phosphorylation of cardiac troponin I (cTnI) and myosin binding protein C (C-protein) and Ca2+ tension relations. Expression of constitutively active Pak1 in rat cardiac myocytes significantly reduced phosphorylation of cTnI and C-protein, which was associated with an increase in sensitivity to Ca2+.
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