TY - JOUR T1 - Role of G Proteins in α<sub>1</sub>-Adrenergic Inhibition of the β-Adrenergically Activated Chloride Current in Cardiac Myocytes JF - Molecular Pharmacology JO - Mol Pharmacol SP - 853 LP - 860 DO - 10.1124/mol.51.5.853 VL - 51 IS - 5 AU - Livia C. Hool AU - Lisa M. Oleksa AU - Robert D. Harvey Y1 - 1997/05/01 UR - http://molpharm.aspetjournals.org/content/51/5/853.abstract N2 - α1-Adrenergic receptor stimulation can inhibit the Cl− current activated by β-adrenergic receptor agonists in guinea-pig ventricular myocytes. We investigated the role of G proteins in mediating this type of α-adrenergic response. The combined α- and β-adrenergic agonist norepinephrine (NE) activated the Cl− current with an EC50 value of 53 nm. Preincubation of myocytes with PTX decreased the EC50 value for NE activation of the Cl−current to 5.9 nm, and addition of the α1-adrenergic receptor antagonist prazosin did not cause any further change in sensitivity to NE. These results suggest that the α1-adrenergic inhibition of β-adrenergic responses is mediated through a PTX-sensitive G protein. However, PTX pretreatment also increased the sensitivity of the Cl− current to the selective β-adrenergic agonist isoproterenol (Iso), which indicates that the PTX treatment increases the sensitivity to β-adrenergic stimulation alone and that this could account for the PTX-induced change in sensitivity to NE. Consistent with this idea, the selective α1-adrenergic receptor agonist methoxamine was still able to inhibit the Cl− current activated by Iso in PTX-treated myocytes. However, the sensitivity to methoxamine was significantly decreased. In control cells, the Cl− current activated by 30 nm Iso was inhibited by methoxamine with an EC50 value of 8.3 μm, but in PTX-treated cells, the EC50 value was 284 μm. The EC50 for methoxamine inhibition was similarly increased when the Cl− current was activated by 300 nmIso. These data suggest that the effects of PTX on α1-adrenergic responses can actually be explained by changes in the sensitivity to β-adrenergic stimulation. To verify the role for a G protein in mediating the inhibitory α1-adrenergic response, we examined the effect of methoxamine on the Cl− current activated in cells dialyzed with the nonhydrolyzable GTP analogue guanosine-5′-O-(3-thio)triphosphate. Pre-exposure to methoxamine resulted in an attenuated response upon subsequent exposure to Iso alone. We conclude that α1-adrenergic inhibition of β-adrenergic responses is mediated by a G protein-dependent mechanism that appears to be PTX-insensitive. ER -