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 p21-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 Ca2+ current (ICaL) and delayed rectifier potassium current (IK) 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 ICaL and IK; (3) inhibition of protein phosphatase 2A increases the enhancement of IK and ICaL by isoproterenol in Ad-Pak1–infected cells; (4) protein phosphatase 2A coimmunoprecipit...