title: Beta-adrenergic modulation of currents produced by rat cardiac Na+ channels expressed in Xenopus laevis oocytes.
abstract: In Xenopus oocytes coexpressing beta 2-adrenergic receptors and the rat cardiac alpha SkM2 Na+ channel, superfusion with 10 microM isoproterenol led to modest (approximately 30%) increases in peak Na+ inward current. Intracellular injection of cAMP and of protein kinase A (PKA) catalytic subunit reproduced this increase, showing that the second messenger pathway involves PKA dependent phosphorylation. Coexpression of the Na+ channel beta 1 subunit had no influence on the modulation. The modulation had little or no effect upon Na+ current waveforms, steady-state activation, steady-state activation, steady-state inactivation, or recovery from both fast and slow inactivation; but maximum Na+ conductance was increased. Mutation of the five major consensus PKA phosphorylation sites on alpha SkM2 did not abolish the observed effect. In parallel experiments, beta-adrenergic stimulation of the neuronal alpha IIA Na+ channel subunit led to an attenuation of Na+ current. It is concluded that (i) the alpha SkM2 subunit might be directly phosphorylated by PKA, but at serine/threonine residue(s) in a cryptic phosphorylation site(s); or that (ii) the modulation might also be mediated by phosphorylation of another, as yet unknown protein(s). The divergent modulation of neuronal and cardiac Na+ channel alpha-subunits suggests that differential physiological modulation by identical second messenger pathways is the evolutionary basis for the isoform diversity within this protein family.
authors.affiliation: Institute of Medical Physics and Biophysics, University of Graz, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Schreibmayer
authors.forename: B
authors.initials: B
authors.lastname: Frohnwieser
authors.forename: N
authors.initials: N
authors.lastname: Dascal
authors.forename: D
authors.initials: D
authors.lastname: Platzer
authors.forename: B
authors.initials: B
authors.lastname: Spreitzer
authors.forename: R
authors.initials: R
authors.lastname: Zechner
authors.forename: R G
authors.initials: RG
authors.lastname: Kallen
authors.forename: H A
authors.initials: HA
authors.lastname: Lester
mesh_terms: D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D018118:Chloride Channels / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005260:Female; D006321:Heart / Q000502:physiology*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D009865:Oocytes / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D015290:Second Messenger Systems; D015222:Sodium Channels / Q000096:biosynthesis / Q000187:drug effects / Q000502:physiology*; D014982:Xenopus laevis
chemical_list: C505032:CFTR protein, human; D018118:Chloride Channels; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; D018343:Receptors, Adrenergic, beta-2; D011994:Recombinant Proteins; D015222:Sodium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D007545:Isoproterenol