Regulation of L-Type Calcium Channel and Delayed Rectifier Potassium Channel Activity by p 21 -Activated Kinase-1 in Guinea Pig Sinoatrial Node Pacemaker Cells

• Published in: Circulation research Vol. 100; no. 9; pp. 1317 - 1327
• Main Authors: Ke, Yunbo, Lei, Ming, Collins, Thomas P., Rakovic, Stevan, Mattick, Paul A.D., Yamasaki, Michiko, Brodie, Mark S., Terrar, Derek A., Solaro, R. John
• Format: Journal Article
• Language: English
• Published: 11.05.2007
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000266742.51389.a4

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.