Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

ADCY9 (Adenylyl Cyclase 9)

  • Ferenc András AntoniEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_140


Historical Background

Adenylyl cyclase (AC) is the enzyme (EC that converts Mg-ATP to adenosine 3′:5′ monophosphate or cyclic AMP and pyrophosphate first reported in 1958 by Sutherland and Rall. Eventually, a membrane-delimited biochemical cascade (Fig. 1) was discovered as the molecular machinery of signal transduction by cell surface receptors via heterotrimeric G proteins (Antoni 2000). The era of gene cloning revealed an unexpectedly complex structure of membrane-bound adenylyl cyclase: a single large polypeptide chain that crosses the plasma membrane 12 times, the catalytic core being formed between two structurally homologous cytoplasmic domains (C1a and C2a) held together by noncovalent interactions (Fig. 2). The crystal structures of these domains in complex with Gsα and the likely mechanisms underlying catalysis have been reported (Tesmer and Sprang 1998). There are nine genes...
This is a preview of subscription content, log in to check access.


  1. Alper S, Laws R, Lackford B, Boyd WA, Dunlap P, Freedman JH, Schwartz DA. Identification of innate immunity genes and pathways using a comparative genomics approach. Proc Natl Acad Sci U S A. 2008;105(19):7016–21.  https://doi.org/10.1073/pnas.0802405105.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Antoni FA, Wiegand U, Black J, Simpson J. Cellular localisation of adenylyl cyclase: a post-genome perspective. Neurochem Res. 2006;31(2):287–95.PubMedCrossRefGoogle Scholar
  3. Antoni FA. Molecular diversity of cyclic AMP signaling. Front Neuroendocrinol. 2000;21:103–32.PubMedCrossRefGoogle Scholar
  4. Antoni FA. New paradigms in cAMP signalling. Mol Cell Endocrinol. 2012;353(1–2):3–9.  https://doi.org/10.1016/j.mce.2011.10.034.CrossRefPubMedPubMedCentralGoogle Scholar
  5. Antoni FA, Barnard RJO, Shipston MJ, Smith SM, Simpson J, Paterson JM. Calcineurin feedback inhibition of agonist-evoked cAMP formation. J Biol Chem. 1995;270:28055–61.PubMedCrossRefGoogle Scholar
  6. Antoni FA, Palkovits M, Simpson J, Smith SM, Leitch AL, Rosie R, Fink G, Paterson JM. Ca2+/calcineurin-inhibited adenylyl cyclase highly abundant in forebrain regions important for learning and memory. J Neurosci. 1998a;18(23):9650–61.PubMedCrossRefGoogle Scholar
  7. Antoni FA, Smith SM, Simpson J, Rosie R, Fink G, Paterson JM. Calcium control of adenylyl cyclase – the calcineurin connection. Adv Second Messenger Phosphoprotein Res. 1998b;32:153–72.PubMedCrossRefGoogle Scholar
  8. Brand CS, Hocker HJ, Gorfe AA, Cavasotto CN, Dessauer CW. Isoform selectivity of adenylyl cyclase inhibitors: characterization of known and novel compounds. J Pharmacol Exp Ther. 2013;347(2):265–75.  https://doi.org/10.1124/jpet.113.208157.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Cumbay MG, Watts VJ. Novel regulatory properties of human type 9 adenylate cyclase. J Pharmacol Exp Ther. 2004;310(1):108–15.  https://doi.org/10.1124/jpet.104.065748.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Dvir M, Strulovich R, Sachyani D, Cohen IB-T, Haitin Y, Dessauer C, Pongs O, Kass R, Hirsch JA, Attali B. Long QT mutations at the interface between KCNQ1 helix C and KCNE1 disrupt I-KS regulation by PKA and PIP2. J Cell Sci. 2014;127(18):3943–55.  https://doi.org/10.1242/jcs.147033.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Hacker BM, Tomlinson JE, Wayman GA, Sultana R, Chan G, Villacres E, Disteche C, Storm DR. Cloning, chromosomal mapping, and regulatory properties of the human type 9 adenylyl cyclase (ADCY9). Genomics. 1998;50(1):97–104.  https://doi.org/10.1006/geno.1998.5293.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Halls ML, Cooper DMF. Regulation by Ca(2+)-signaling pathways of adenylyl cyclases. Cold Spring Harb Perspect Biol. 2011;3(1).  https://doi.org/10.1101/cshperspect.a004143.Google Scholar
  13. Haunsø A, Simpson J, Antoni FA. Small ligands modulating the activity of mammalian adenylyl cyclases: A novel mode of inhibition by calmidazolium. Mol Pharmacol. 2003;63:624–31.PubMedCrossRefGoogle Scholar
  14. Houslay MD. Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Science. 2010;35(2):91–100.  https://doi.org/10.1016/j.tibs.2009.09.007.CrossRefGoogle Scholar
  15. Johannessen CM, Johnson LA, Piccioni F, Townes A, Frederick DT, Donahue MK, Narayan R, Flaherty KT, Wargo JA, Root DE, Garraway LA. A melanocyte lineage program confers resistance to MAP kinase pathway inhibition. Nature. 2013;504(7478):138–42.  https://doi.org/10.1038/nature12688.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Lefkimmiatis K, Zaccolo M. cAMP signaling in subcellular compartments. Pharmacol Ther. 2014;143(3):295–304.  https://doi.org/10.1016/j.pharmthera.2014.03.008.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Li Y, Chen L, Kass RS, Dessauer CW. The A-kinase anchoring protein Yotiao facilitates complex formation between adenylyl cyclase type 9 and the IKs potassium channel in heart. J Biol Chem. 2012;287(35):29815–24.  https://doi.org/10.1074/jbc.M112.380568.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Mons N, Segu L, Nogues X, Buhot M. Effects of age and spatial learning on adenylyl cyclase mRNA expression in the mouse hippocampus. Neurobiol Aging. 2004;25(8):1095–106.PubMedCrossRefGoogle Scholar
  19. Niesor EJ, Benghozi R, Amouyel P, Ferdinand KC, Schwartz GG. Adenylyl cyclase 9 polymorphisms reveal potential link to HDL function and cardiovascular events in multiple pathologies: Potential implications in sickle cell disease. Cardiovasc Drugs Ther. 2015;29(6):563–72.  https://doi.org/10.1007/s10557-015-6626-1.CrossRefPubMedPubMedCentralGoogle Scholar
  20. Osteen JD, Sampson KJ, Kass RS. The cardiac IKs channel, complex indeed. Proc Natl Acad Sci U S A. 2010;107(44):18751–2.  https://doi.org/10.1073/pnas.1014150107.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Paterson JM, Smith SM, Simpson J, Grace OC, Sosunov AA, Bell J, Antoni FA. Characterisation of human adenylyl cyclase IX reveals inhibition by Ca2+/calcineurin and differential mRNA polyadenylation. J Neurochem. 2000;75(4):1358–67.PubMedCrossRefGoogle Scholar
  22. Piggott LA, Bauman AL, Scott JD, Dessauer CW. The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain. Proc Natl Acad Sci U S A. 2008;105(37):13835–40.  https://doi.org/10.1073/pnas.0712100105.CrossRefPubMedPubMedCentralGoogle Scholar
  23. Premont RT, Matsuoka I, Mattei M-G, Pouille Y, Defer N, Hanoune J. Identification and characterization of a widely expressed from of adenylyl cyclase. J Biol Chem. 1996;271:13900–7.PubMedCrossRefGoogle Scholar
  24. Simpson J, Morrice N, Chen P, Antoni FA. Regulation of adenylyl cyclase 9 by cyclin-dependent protein kinase 5 (cdk5). Bioscience 2006. Glasgow: Portland Press; 2006. 0449.Google Scholar
  25. Small K, Brown K, Theiss C, Seman C, Weiss S, Liggett S. An Ile to Met polymorphism in the catalytic domain of adenylyl cyclase type 9 confers reduced beta2-adrenergic receptor stimulation. Pharmacogenetics. 2003;13(9):535–41.PubMedCrossRefGoogle Scholar
  26. Tardif JC, Rheaume E, Lemieux Perreault LP, Gregoire JC, Feroz Zada Y, Asselin G, Provost S, Barhdadi A, Rhainds D, L'Allier PL, Ibrahim R, Upmanyu R, Niesor EJ, Benghozi R, Suchankova G, Laghrissi-Thode F, Guertin MC, Olsson AG, Mongrain I, Schwartz GG, Dube MP. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015;8(2):372–82.  https://doi.org/10.1161/circgenetics.114.000663.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Tesmer J, Sprang S. The structure, catalytic mechanism and regulation of adenylyl cyclase. Curr Opin Struct Biol. 1998;8(6):713–9.PubMedCrossRefGoogle Scholar
  28. Toyota T, Yamada K, Saito K, Detera-Wadleigh S, Yoshikawa T. Association analysis of adenylate cyclase type 9 gene using pedigree disequilibrium test in bipolar disorder. Mol Psychiatry. 2002;7(5):450–2.PubMedCrossRefGoogle Scholar
  29. Yan SZ, Huang ZH, Andrews RK, Tang WJ. Conversion of forskolin-insensitive to forskolin-sensitive (mouse-type IX) adenylyl cyclase. Mol Pharmacol. 1998;53(2):182–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre for Integrative PhysiologyUniversity of EdinburghEdinburghUK