title: AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K(+) currents in ventricular myocytes following myocardial infarction.
abstract: The Ca(2+)-responsive phosphatase calcineurin/protein phosphatase 2B dephosphorylates the transcription factor NFATc3. In the myocardium activation of NFATc3 down-regulates the expression of voltage-gated K(+) (Kv) channels after myocardial infarction (MI). This prolongs action potential duration and increases the probability of arrhythmias. Although recent studies infer that calcineurin is activated by local and transient Ca(2+) signals the molecular mechanism that underlies the process is unclear in ventricular myocytes. Here we test the hypothesis that sequestering of calcineurin to the sarcolemma of ventricular myocytes by the anchoring protein AKAP150 is required for acute activation of NFATc3 and the concomitant down-regulation of Kv channels following MI. Biochemical and cell based measurements resolve that approximately 0.2% of the total calcineurin activity in cardiomyocytes is associated with AKAP150. Electrophysiological analyses establish that formation of this AKAP150-calcineurin signaling dyad is essential for the activation of the phosphatase and the subsequent down-regulation of Kv channel currents following MI. Thus AKAP150-mediated targeting of calcineurin to sarcolemmal micro-domains in ventricular myocytes contributes to the local and acute gene remodeling events that lead to the down-regulation of Kv currents.
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, United States.
authors.forename: Madeline
authors.initials: M
authors.lastname: Nieves-Cintrón
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA, United States.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Hirenallur-Shanthappa
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA, United States.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Nygren
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA, United States.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Hinke
authors.affiliation: Department of Pharmacology, University of Colorado Denver, Aurora, CO, United States.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Dell'Acqua
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA, United States.
authors.forename: Lorene K
authors.initials: LK
authors.lastname: Langeberg
authors.affiliation: Department of Pharmacology, University of California, Davis, CA, United States.
authors.forename: Manuel
authors.initials: M
authors.lastname: Navedo
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, CA, United States. Electronic address: lfsantana@ucdavis.edu.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Santana
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA, United States. Electronic address: scottjdw@uw.edu.
authors.forename: John D
authors.initials: JD
authors.lastname: Scott
mesh_terms: D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000378:metabolism*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000473:pathology*; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects
chemical_list: D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D050778:NFATC Transcription Factors; D024642:Potassium Channels, Voltage-Gated; D010656:Phenylephrine; D019703:Calcineurin
keywords: A-kinase anchoring protein AKAP; Acute transcriptional response; Calcineurin; Myocardial infarction