Novel bradykinin signaling in adult rat cardiac myocytes through activation of p21-activated kinase.
Although bradykinin (BK) is known to exert effects on the myocardium, its intracellular signaling pathways remain poorly understood. Experiments in other cell types indicated that p21-activated kinase-1 (Pak1), a Ser/Thr kinase downstream of small monomeric G proteins, is activated by BK. We previously reported that the expression of active Pak1 in adult cardiac myocytes induced activation of protein phosphatase 2A and dephosphorylation of myofilament proteins (Ke et al. Circ Res 94: 194-200, 2004). In experiments reported here, we tested the hypothesis that BK signals altered protein phosphorylation in adult rat cardiac myocytes through the activation and translocation of Pak1. Treatment of myocytes with BK resulted in the activation of Pak1 as demonstrated by increased autophosphorylation at Thr423 and a diminished striated localization, which is present in the basal state. BK induced dephosphorylation of both cardiac troponin I and phospholamban. Treatment of isolated myocytes with BK also blunted the effect of isoproterenol to enhance peak Ca(2+) and relaxation of Ca(2+) transients. Protein phosphatase 2A was demonstrated to associate with both Pak 1 and phospholamban. Our studies indicate a novel signaling mechanism for BK in adult rat cardiac myocytes and support our hypothesis that Pak 1 is a significant regulator of phosphatase activity in the heart.
Ke
Yunbo
Y
Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, USA.
Sheehan
Katherine A
KA
Egom
E Eroume A
EE
Lei
Ming
M
Solaro
R John
RJ
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D019210:Troponin I / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D001920:Bradykinin; D002135:Calcium-Binding Proteins; D007545:Isoproterenol; D054648:Protein Phosphatase 2; D019210:Troponin I; D054462:p21-Activated Kinases; D000099211:Phospholamban; C515906:Pak1 protein, rat