Tyrosine phosphatase inhibitors selectively antagonize beta-adrenergic receptor-dependent regulation of cardiac ion channels

beta -Adrenergic receptor stimulation regulates the activity of several dif ferent cardiac ion channels through an adenylate cyclase/cAMP/protein kinas e A-dependent mechanism. Previous work has suggested that basal tyrosine ki nase activity attenuates the beta -adrenergic responsiveness of these cardi ac ion channels, supporting the idea that tyrosine phosphorylation exerts a n inhibitory effect at some point in the common signaling pathway. To deter mine which element in the beta -adrenergic pathway is regulated by tyrosine kinase activity, we studied the effects of various protein tyrosine phosph atase (PTP) inhibitors on the cAMP-dependent regulation of the L-type Ca2current in guinea pig ventricular myocytes. Three such compounds, sodium or thovanadate, peroxovanadate, and bpV(phen), had no effect on the basal Ca2 current, yet each caused a pronounced inhibition of the Ca2+ current stimu lated by the beta -adrenergic receptor agonist isoproterenol. These observa tions are consistent with the idea that basal tyrosine kinase activity is c apable of inhibiting beta -adrenergic responses. However, these PTP inhibit ors had no effect on cAMP-dependent stimulation of the Ca2+ current via act ivation of adenylate cyclase with forskolin or activation of H-2-histaminer gic receptors with histamine. These results are consistent with the idea th at inhibition of PTP activity produces an inhibitory effect involving a tyr osine kinase-dependent mechanism acting selectively at the level of the bet a -adrenergic receptor. This signaling mechanism does not seem to be linked to tyrosine kinase activity associated with insulin and insulin-like growt h factor receptors, because acute exposure to agonists of these receptors d id not inhibit isoproterenol regulation of the Ca2+ current.