TY - JOUR T1 - Novel Regulatory Properties of Human Type 9 Adenylate Cyclase JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 108 LP - 115 DO - 10.1124/jpet.104.065748 VL - 310 IS - 1 AU - Medhane G. Cumbay AU - Val J. Watts Y1 - 2004/07/01 UR - http://jpet.aspetjournals.org/content/310/1/108.abstract N2 - Nine membrane-bound members of the mammalian adenylate cyclase family have been identified. The least characterized and most divergent in sequence of the nine adenylate cyclase isoforms is AC9. Stimulation by Gαs and inhibition by Ca2+/calcineurin are two modes of regulation that have been reported for AC9. We explored the possibility of additional modes of regulation of human AC9. We now report that quinpirole activation of the inhibitory G protein-coupled D2L dopamine receptor inhibits Gαs stimulation of AC9 by approximately 50%. The effects of quinpirole were reversed by the D2 antagonist spiperone and by pertussis toxin pretreatment. We also report the first evidence for regulation of AC9 by protein kinase C (PKC). Specifically, phorbol ester activation of PKC significantly attenuated (∼50%) Gαs-stimulated AC9 activity. The effect of PKC activation on AC9 was reversed by the PKC inhibitor bisindolylmaleimide. Gαs-stimulated cyclic accumulation was reduced more by simultaneous addition of both quinpirole and phorbol 12-myristate 13-acetate than by either drug alone. Additional studies investigated the role of glycosylation on AC9 activity. The results show that blocking glycosylation of AC9 significantly attenuates Gαs stimulation. In contrast, the ability of PKC and Gαi/o to negatively regulate AC9 did not seem to be affected by the glycosylation state of AC9. These observations demonstrate the diverse regulatory features of AC9 and the ability of AC9 to integrate multiple signals. The American Society for Pharmacology and Experimental Therapeutics ER -