title: Regulation of L-type calcium channel and delayed rectifier potassium channel activity by p21-activated kinase-1 in guinea pig sinoatrial node pacemaker cells.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics and Center for Cardiovascular Research, University of Illinois at Chicago, IL, USA.
authors.forename: Yunbo
authors.initials: Y
authors.lastname: Ke
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Collins
authors.forename: Stevan
authors.initials: S
authors.lastname: Rakovic
authors.forename: Paul A D
authors.initials: PA
authors.lastname: Mattick
authors.forename: Michiko
authors.initials: M
authors.lastname: Yamasaki
authors.forename: Mark S
authors.initials: MS
authors.lastname: Brodie
authors.forename: Derek A
authors.initials: DA
authors.lastname: Terrar
authors.forename: R John
authors.initials: RJ
authors.lastname: Solaro
mesh_terms: 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
chemical_list: 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