calyculin-a and zinterol

In contrast to beta(1)-adrenoreceptor (beta(1)-AR) signaling, beta(2)-AR stimulation in cardiomyocytes augments L-type Ca(2+) current in a cAMP-dependent protein kinase (PKA)-dependent manner but fails to phosphorylate phospholamban, indicating that the beta(2)-AR-induced cAMP/PKA signaling is highly localized. Here we show that inhibition of G(i) proteins with pertussis toxin (PTX) permits a full phospholamban phosphorylation and a de novo relaxant effect following beta(2)-AR stimulation, converting the localized beta(2)-AR signaling to a global signaling mode similar to that of beta(1)-AR. Thus, beta(2)-AR-mediated G(i) activation constricts the cAMP signaling to the sarcolemma. PTX treatment did not significantly affect the beta(2)-AR-stimulated PKA activation. Similar to G(i) inhibition, a protein phosphatase inhibitor, calyculin A (3 x 10(-8) M), selectively enhanced the beta(2)-AR but not beta(1)-AR-mediated contractile response. Furthermore, PTX and calyculin A treatment had a non-additive potentiating effect on the beta(2)-AR-mediated positive inotropic response. These results suggest that the interaction of the beta(2)-AR-coupled G(i) and G(s) signaling affects the local balance of protein kinase and phosphatase activities. Thus, the additional coupling of beta(2)-AR to G(i) proteins is a key factor causing the compartmentalization of beta(2)-AR-induced cAMP signaling.

Topics: Adrenergic beta-2 Receptor Agonists; Adrenergic beta-2 Receptor Antagonists; Animals; Calcium Channels; Calcium Channels, L-Type; Calcium-Binding Proteins; Cell Size; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Ethanolamines; GTP-Binding Protein alpha Subunits, Gi-Go; Heart; Heart Ventricles; Marine Toxins; Myocardial Contraction; Myocardium; Oxazoles; Pertussis Toxin; Phosphorylation; Propanolamines; Rats; Receptors, Adrenergic, beta-2; Signal Transduction; Thionucleotides; Vasoconstrictor Agents; Virulence Factors, Bordetella