RT Journal Article
SR Electronic
T1 Tyrosine Phosphatase Inhibitors Selectively Antagonize β-Adrenergic Receptor-Dependent Regulation of Cardiac Ion Channels
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1213
OP 1221
DO 10.1124/mol.58.6.1213
VO 58
IS 6
A1 Carl Sims
A1 Jason Chiu
A1 Robert D. Harvey
YR 2000
UL http://molpharm.aspetjournals.org/content/58/6/1213.abstract
AB β-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 β-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 β-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 Ca2+ current in guinea pig ventricular myocytes. Three such compounds, sodium orthovanadate, peroxovanadate, and bpV(phen), had no effect on the basal Ca2+ current, yet each caused a pronounced inhibition of the Ca2+ current stimulated by the β-adrenergic receptor agonist isoproterenol. These observations are consistent with the idea that basal tyrosine kinase activity is capable of inhibiting β-adrenergic responses. However, these PTP inhibitors had no effect on cAMP-dependent stimulation of the Ca2+ current via activation of adenylate cyclase with forskolin or activation of H2-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 β-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 Ca2+ current.