Regulation of L-type calcium channel and delayed rectifier potassium channel activity by p21-activated kinase-1 in guinea pig sinoatrial node pacemaker cells.
Phosphorylation of ion channels plays an important role in the regulation of cardiac function, but signaling mechanisms controlling dephosphorylation are not well understood. We have tested the hypothesis that p(21)-activated kinase-1 (Pak1), a serine-threonine protein kinase regulated by Ras-related small G proteins, regulates sinoatrial node (SAN) ion channel activity through a mechanism involving protein phosphatase 2A. We report a novel role of Pak1-mediated signaling in attenuating isoproterenol-induced enhancement of L-type Ca(2+) current (I(CaL)) and delayed rectifier potassium current (I(K)) in guinea pig SAN pacemaker cells. We demonstrate that in guinea pig SAN: (1) there is abundant expression of endogenous Pak1 in pacemaker cells; (2) expression of constitutively active Pak1 depresses isoproterenol-induced upregulation of I(CaL) and I(K); (3) inhibition of protein phosphatase 2A increases the enhancement of I(K) and I(CaL) by isoproterenol in Ad-Pak1-infected cells; (4) protein phosphatase 2A coimmunoprecipitates with endogenous Pak1 in SAN tissue; and (5) expression of constitutively active Pak1 suppresses the chronotropic action of isoproterenol on pacemaker activity of intact SAN preparations. In conclusion, our data demonstrate that a Pak1 signaling pathway exists in cardiac pacemaker cells and that this novel pathway plays a role in the regulation of ion channel activity.
Ke
Yunbo
Y
Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL, USA.
Lei
Ming
M
Collins
Thomas P
TP
Rakovic
Stevan
S
Mattick
Paul A D
PA
Yamasaki
Michiko
M
Brodie
Mark S
MS
Terrar
Derek A
DA
Solaro
R John
RJ
D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology*; D051668:Delayed Rectifier Potassium Channels / Q000502:physiology*; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000502:physiology; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012849:Sinoatrial Node / Q000378:metabolism*; D014162:Transfection; D054462:p21-Activated Kinases
D020746:Calcium Channels, L-Type; D051668:Delayed Rectifier Potassium Channels; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D007545:Isoproterenol