Vol. 58, Issue 6, 1213-1221, December 2000

Tyrosine Phosphatase Inhibitors Selectively Antagonize -Adrenergic Receptor-Dependent Regulation of Cardiac Ion Channels

Carl Sims, Jason Chiu, and Robert D. Harvey

Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio

-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 -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 -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 -adrenergic receptor agonist isoproterenol. These observations are consistent with the idea that basal tyrosine kinase activity is capable of inhibiting -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 -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.