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Molecular Pharmacology

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Research ArticleArticle

Insights into the Regulatory Properties of Human Adenylyl Cyclase Type 9

Tanya A. Baldwin, Yong Li, Cameron S. Brand, Val J. Watts and Carmen W. Dessauer
Molecular Pharmacology April 2019, 95 (4) 349-360; DOI: https://doi.org/10.1124/mol.118.114595
Tanya A. Baldwin
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, Texas (T.A.B., Y.L., C.S.B., C.W.D.); and Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (V.J.W.)
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Yong Li
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, Texas (T.A.B., Y.L., C.S.B., C.W.D.); and Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (V.J.W.)
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Cameron S. Brand
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, Texas (T.A.B., Y.L., C.S.B., C.W.D.); and Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (V.J.W.)
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Val J. Watts
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, Texas (T.A.B., Y.L., C.S.B., C.W.D.); and Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (V.J.W.)
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Carmen W. Dessauer
Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center, Houston, Texas (T.A.B., Y.L., C.S.B., C.W.D.); and Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana (V.J.W.)
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Abstract

Membrane-bound adenylyl cyclase (AC) isoforms have distinct regulatory mechanisms that contribute to their signaling specificity and physiologic roles. Although insight into the physiologic relevance of AC9 has progressed, the understanding of AC9 regulation is muddled with conflicting studies. Currently, modes of AC9 regulation include stimulation by Gαs, protein kinase C (PKC) βII, or calcium-calmodulin kinase II (CaMKII) and inhibition by Gαi/o, novel PKC isoforms, or calcium-calcineurin. Conversely, the original cloning of human AC9 reported that AC9 is insensitive to Gαi inhibition. The purpose of our study was to clarify which proposed regulators of AC9 act directly or indirectly, particularly with respect to Gαi/o. The proposed regulators, including G proteins (Gαs, Gαi, Gαo, Gβγ), protein kinases (PKCβII, CaMKII), and forskolin, were systematically evaluated using classic in vitro AC assays and cell-based cAMP accumulation assays in COS-7 cells. Our studies show that AC9 is directly regulated by Gαs with weak conditional activation by forskolin; other modes of proposed regulation either occur indirectly or possibly require additional scaffolding proteins to facilitate regulation. We also show that AC9 contributes to basal cAMP production; knockdown or knockout of endogenous AC9 reduces basal AC activity in COS-7 cells and splenocytes. Importantly, although AC9 is not directly inhibited by Gαi/o, it can heterodimerize with Gαi/o-regulated isoforms, AC5 and AC6.

Footnotes

    • Received September 20, 2018.
    • Accepted January 23, 2019.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants R01-GM60419 and T32-GM089657-05].

  • https://doi.org/10.1124/mol.118.114595.

  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 95 (4)
Molecular Pharmacology
Vol. 95, Issue 4
1 Apr 2019
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Research ArticleArticle

Direct Regulation of AC9

Tanya A. Baldwin, Yong Li, Cameron S. Brand, Val J. Watts and Carmen W. Dessauer
Molecular Pharmacology April 1, 2019, 95 (4) 349-360; DOI: https://doi.org/10.1124/mol.118.114595

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Research ArticleArticle

Direct Regulation of AC9

Tanya A. Baldwin, Yong Li, Cameron S. Brand, Val J. Watts and Carmen W. Dessauer
Molecular Pharmacology April 1, 2019, 95 (4) 349-360; DOI: https://doi.org/10.1124/mol.118.114595
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