Tyrosine phosphatase inhibitors selectively antagonize beta-adrenergic receptor-dependent regulation of cardiac ion channels.
beta-Adrenergic receptor stimulation regulates the activity of several different cardiac ion channels through an adenylate cyclase/cAMP/protein kinase A-dependent mechanism. Previous work has suggested that basal tyrosine kinase activity attenuates the beta-adrenergic responsiveness of these cardiac ion channels, supporting the idea that tyrosine phosphorylation exerts an inhibitory effect at some point in the common signaling pathway. To determine which element in the beta-adrenergic pathway is regulated by tyrosine kinase activity, we studied the effects of various protein tyrosine phosphatase (PTP) inhibitors on the cAMP-dependent regulation of the L-type Ca(2+) current in guinea pig ventricular myocytes. Three such compounds, sodium orthovanadate, peroxovanadate, and bpV(phen), had no effect on the basal Ca(2+) current, yet each caused a pronounced inhibition of the Ca(2+) current stimulated by the beta-adrenergic receptor agonist isoproterenol. These observations are consistent with the idea that basal tyrosine kinase activity is capable of inhibiting beta-adrenergic responses. However, these PTP inhibitors had no effect on cAMP-dependent stimulation of the Ca(2+) current via activation of adenylate cyclase with forskolin or activation of H(2)-histaminergic receptors with histamine. These results are consistent with the idea that inhibition of PTP activity produces an inhibitory effect involving a tyrosine kinase-dependent mechanism acting selectively at the level of the beta-adrenergic receptor. This signaling mechanism does not seem to be linked to tyrosine kinase activity associated with insulin and insulin-like growth factor receptors, because acute exposure to agonists of these receptors did not inhibit isoproterenol regulation of the Ca(2+) current.
Sims
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Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio 44106-4970, USA.
Chiu
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Harvey
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D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D014638:Vanadates / Q000494:pharmacology
D020746:Calcium Channels, L-Type; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D010618:Phenanthrolines; D011943:Receptors, Adrenergic, beta; C069276:peroxovanadate; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014638:Vanadates; C102120:bisperoxo(1,10-phenanthroline)oxovanadate(1-); D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases