Heterologous desensitization and reduced G protein ADP-ribosylation following exposure to alpha 2-adrenoceptor and muscarinic receptor agonists.

We investigated the acute and chronic effects of alpha 2-adrenoceptor and muscarinic receptor agonists on dihydropyridine-sensitive voltage-dependent Ca2+ channels in spinal cord-dorsal root ganglion cocultures. Clonidine and oxotremorine inhibited the voltage-dependent Ca2+ influx (42 +/- 2% and 35 +/- 6% with 100 microM, respectively). The respective antagonists, yohimbine and atropine, abolished these effects. Pertussis toxin attenuated the inhibitory effects of clonidine and oxotremorine on Ca2+ influx, demonstrating involvement of G proteins in the transduction process. Chronic treatment with clonidine or oxotremorine desensitized the Ca2+ channel response to the agonist applied as well as to the other receptor agonist (heterologous desensitization). Such treatment with clonidine or oxotremorine decreased the pertussis toxin-catalyzed ADP-ribosylation of Gi alpha and G(o) alpha subunits, an effect which could be largely reversed by the detergent Lubrol PX. Yohimbine and atropine blocked the effects of clonidine or oxotremorine on pertussis toxin-catalyzed ADP-ribosylation. Results suggest that alpha 2-adrenoceptor and muscarinic receptors couple to the dihydropyridine-sensitive voltage-dependent Ca2+ channels via pertussis toxin-sensitive G proteins. Chronic agonist treatment leads to heterologous desensitization and to a reduced capacity of Gi and G(o) to undergo pertussis toxin-catalyzed ADP-ribosylation.