QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.104.065748v1 310/1/108    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cumbay, M. G. Articles by Watts, V. J. Search for Related Content PubMed PubMed Citation Articles by Cumbay, M. G. Articles by Watts, V. J.

CELLULAR AND MOLECULAR

Novel Regulatory Properties of Human Type 9 Adenylate Cyclase

Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana

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 G_s 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 D_2L dopamine receptor inhibits G_s 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%) G_s-stimulated AC9 activity. The effect of PKC activation on AC9 was reversed by the PKC inhibitor bisindolylmaleimide. G_s-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 G_s stimulation. In contrast, the ability of PKC and G_i/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.

Address correspondence to: Dr. Val J. Watts, Purdue University, Medicinal Chemistry and Molecular Pharmacology, 575 Stadium Mall Dr., West Lafayette, IN 47907. E-mail: wattsv{at}pharmacy.purdue.edu

This article has been cited by other articles:

				D. Willoughby and D. M. F. Cooper Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains Physiol Rev, July 1, 2007; 87(3): 965 - 1010. [Abstract] [Full Text] [PDF]