title: p38α regulates SERCA2a function.
abstract: cAMP-dependent protein kinase (PKA) regulates the L-type calcium channel, the ryanodine receptor, and phospholamban (PLB) thereby increasing inotropy. Cardiac contractility is also regulated by p38 MAPK, which is a negative regulator of cardiac contractile function. The aim of this study was to identify the mechanism mediating the positive inotropic effect of p38 inhibition. Isolated adult and neonatal cardiomyocytes and perfused rat hearts were utilized to investigate the molecular mechanisms regulated by p38. PLB phosphorylation was enhanced in cardiomyocytes by chemical p38 inhibition, by overexpression of dominant negative p38α and by p38α RNAi, but not with dominant negative p38β. Treatment of cardiomyocytes with dominant negative p38α significantly decreased Ca(2+)-transient decay time indicating enhanced sarco/endoplasmic reticulum Ca(2+)-ATPase function and increased cardiomyocyte contractility. Analysis of signaling mechanisms involved showed that inhibition of p38 decreased the activity of protein phosphatase 2A, which renders protein phosphatase inhibitor-1 phosphorylated and thereby inhibits PP1. In conclusion, inhibition of p38α enhances PLB phosphorylation and diastolic Ca(2+) uptake. Our findings provide evidence for novel mechanism regulating cardiac contractility upon p38 inhibition.
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Kaikkonen
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Magga
authors.affiliation: Biocenter Oulu, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Veli-Pekka
authors.initials: VP
authors.lastname: Ronkainen
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Koivisto
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Ábel
authors.initials: Á
authors.lastname: Perjes
authors.affiliation: Temple University School of Medicine, MERB 9th floor, 3500 N Broad St., Philadelphia, PA 19140, USA.
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.affiliation: Research Institute of Internal Medicine, Sognsvannsveien 20, 0027 Oslo, Norway; Department of Cardiology, Oslo University Hospital Rikshospitalet, Sognsvannsveien 20, 0027 Oslo, Norway; Center for Heart Failure Research, University of Oslo, Norway.
authors.forename: Leif Erik
authors.initials: LE
authors.lastname: Vinge
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Kilpiö
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Jani
authors.initials: J
authors.lastname: Aro
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Ulvila
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Alakoski
authors.affiliation: Department of Psychiatry, University of Texas, Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9070, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: Bibb
authors.affiliation: Heart Institute, Medical School, University of Pécs, 13 Ifjúság St., 7624 Pécs Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Szokodi
authors.affiliation: Temple University School of Medicine, MERB 9th floor, 3500 N Broad St., Philadelphia, PA 19140, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland; Dept. of Pharmacology and Toxicology, Faculty of Pharmacy; University of Helsinki, Viikinkaari 9, FI-00014 Helsinki, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Ruskoaho
authors.affiliation: Dept. of Pharmacology and Toxicology, Institute of Biomedicine, University of Oulu, P.O. BOX 5000, FI-90014 Oulu, Finland; Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Finland. Electronic address: Risto.Kerkela@oulu.fi.
authors.forename: Risto
authors.initials: R
authors.lastname: Kerkelä
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D009119:Muscle Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000494:pharmacology; D000099211:Phospholamban
chemical_list: D002118:Calcium; D002135:Calcium-Binding Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D048051:p38 Mitogen-Activated Protein Kinases; D000099211:Phospholamban
keywords: AMVM; ARVM; Cardiac contractility; ET-1; G protein coupled receptor kinase; GRK; I-1; MAPK; NRVM; OA; PLB; PP1; PP2A; Phospholamban; SERCA2a; adult mouse ventricular myocyte; adult rat ventricular myocyte; dn; dominant negative; endothelin-1; inhibitor-1; mitogen-activated protein kinase; neonatal rat ventricular myocyte; okadaic acid; p38; phospholamban; protein phosphatase-1; protein phosphatase-2A; sarco/endoplasmic reticulum Ca(2+) ATPase