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(Circulation Research. 2007;100:1317.)
© 2007 American Heart Association, Inc.

Cellular Biology

Regulation of L-Type Calcium Channel and Delayed Rectifier Potassium Channel Activity by p²¹-Activated Kinase-1 in Guinea Pig Sinoatrial Node Pacemaker Cells

Yunbo Ke^*, Ming Lei^*, Thomas P. Collins, Stevan Rakovic, Paul A.D. Mattick, Michiko Yamasaki, Mark S. Brodie, Derek A. Terrar, R. John Solaro

From the Department of Physiology and Biophysics and Center for Cardiovascular Research (Y.K., M.S.B., R.J.S.), University of Illinois at Chicago; Division of Cardiovascular and Endocrine Sciences (M.L.), University of Manchester, UK; and Department of Pharmacology (T.P.C., S.R., P.A.D.M., M.Y., D.A.T.), University of Oxford, UK.

Correspondence to Dr Ming Lei, MD, PhD, Division of Cardiovascular and Endocrine Sciences, University of Manchester, Manchester M13 9XX, UK. E-mail ming.lei{at}manchester.ac.uk

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 (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.

Key Words: p²¹-activated kinase-1 • pacemaking • sinoatrial node • L-type calcium channels • voltage-dependent potassium channels

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