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Adenylyl cyclases (ACs) C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
Adenylyl cyclase, E.C. 4.6.1.1, converts ATP to cyclic AMP and pyrophosphate. Mammalian membrane-bound adenylyl cyclases (nomenclature as approved by the NC-IUPHAR Subcommittee on Adenylyl cyclases [8]) are typically made up of two clusters of six TM domains separating two intracellular, overlapping catalytic domains that are the target for the nonselective activators forskolin, NKH477 (except AC9, [20]) and Gαs (the stimulatory G protein α subunit). Adenosine and its derivatives (e.g. 2',5'-dideoxyadenosine), acting through the P-site, appear to be physiological inhibitors of adenylyl cyclase activity [26]. Three families of adenylyl cyclase are distinguishable: calmodulin (CALM2, CALM3, CALM1, P62158)-stimulated (AC1, AC3 and AC8), Ca2+-inhibitable (AC5, AC6 and AC9) and Ca2+-insensitive (AC2, AC4 and AC7) forms.
Enzymes
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AC1 (adenylyl cyclase 1) C Show summary »« Hide summary
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AC2 (adenylyl cyclase 2) C Show summary »« Hide summary
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AC3 (adenylyl cyclase 3) C Show summary »« Hide summary
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AC4 (adenylyl cyclase 4) C Show summary »« Hide summary
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AC5 (adenylyl cyclase 5) C Show summary »« Hide summary
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AC6 (adenylyl cyclase 6) C Show summary »« Hide summary
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AC7 (adenylyl cyclase 7) C Show summary »« Hide summary
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AC8 (adenylyl cyclase 8) C Show summary »« Hide summary
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AC9 (adenylyl cyclase 9) C Show summary »« Hide summary
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Further reading
* Key recommended reading is highlighted with an asterisk
* Dessauer CW, Watts VJ, Ostrom RS, Conti M, Dove S, Seifert R. (2017) International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. Pharmacol. Rev., 69 (2): 93-139. [PMID:28255005]
Johnstone TB, Agarwal SR, Harvey RD, Ostrom RS. (2018) cAMP Signaling Compartmentation: Adenylyl Cyclases as Anchors of Dynamic Signaling Complexes. Mol. Pharmacol., 93 (4): 270-276. [PMID:29217670]
References
1. Brand CS, Hocker HJ, Gorfe AA, Cavasotto CN, Dessauer CW. (2013) Isoform selectivity of adenylyl cyclase inhibitors: characterization of known and novel compounds. J. Pharmacol. Exp. Ther., 347 (2): 265-75. [PMID:24006339]
2. Buck J, Sinclair ML, Schapal L, Cann MJ, Levin LR. (1999) Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. Proc. Natl. Acad. Sci. U.S.A., 96 (1): 79-84. [PMID:9874775]
3. Cali JJ, Zwaagstra JC, Mons N, Cooper DM, Krupinski J. (1994) Type VIII adenylyl cyclase. A Ca2+/calmodulin-stimulated enzyme expressed in discrete regions of rat brain. J. Biol. Chem., 269 (16): 12190-5. [PMID:8163524]
4. Chen J, Iyengar R. (1993) Inhibition of cloned adenylyl cyclases by mutant-activated Gi-alpha and specific suppression of type 2 adenylyl cyclase inhibition by phorbol ester treatment. J. Biol. Chem., 268 (17): 12253-6. [PMID:8389756]
5. Chen Y, Cann MJ, Litvin TN, Iourgenko V, Sinclair ML, Levin LR, Buck J. (2000) Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor. Science, 289 (5479): 625-8. [PMID:10915626]
6. Chen Y, Harry A, Li J, Smit MJ, Bai X, Magnusson R, Pieroni JP, Weng G, Iyengar R. (1997) Adenylyl cyclase 6 is selectively regulated by protein kinase A phosphorylation in a region involved in Galphas stimulation. Proc. Natl. Acad. Sci. U.S.A., 94 (25): 14100-4. [PMID:9391159]
7. Choi EJ, Xia Z, Storm DR. (1992) Stimulation of the type III olfactory adenylyl cyclase by calcium and calmodulin. Biochemistry, 31 (28): 6492-8. [PMID:1633161]
8. Dessauer CW, Watts VJ, Ostrom RS, Conti M, Dove S, Seifert R. (2017) International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. Pharmacol. Rev., 69 (2): 93-139. [PMID:28255005]
9. Gao BN, Gilman AG. (1991) Cloning and expression of a widely distributed (type IV) adenylyl cyclase. Proc. Natl. Acad. Sci. U.S.A., 88 (22): 10178-82. [PMID:1946437]
10. Hess KC, Jones BH, Marquez B, Chen Y, Ord TS, Kamenetsky M, Miyamoto C, Zippin JH, Kopf GS, Suarez SS et al.. (2005) The "soluble" adenylyl cyclase in sperm mediates multiple signaling events required for fertilization. Dev. Cell, 9 (2): 249-59. [PMID:16054031]
11. Hill J, Howlett A, Klein C. (2000) Nitric oxide selectively inhibits adenylyl cyclase isoforms 5 and 6. Cell. Signal., 12 (4): 233-7. [PMID:10781930]
12. Ishikawa Y, Katsushika S, Chen L, Halnon NJ, Kawabe J, Homcy CJ. (1992) Isolation and characterization of a novel cardiac adenylylcyclase cDNA. J. Biol. Chem., 267 (19): 13553-7. [PMID:1618857]
13. Iwami G, Kawabe J, Ebina T, Cannon PJ, Homcy CJ, Ishikawa Y. (1995) Regulation of adenylyl cyclase by protein kinase A. J. Biol. Chem., 270 (21): 12481-4. [PMID:7759492]
14. Jacobowitz O, Chen J, Premont RT, Iyengar R. (1993) Stimulation of specific types of Gs-stimulated adenylyl cyclases by phorbol ester treatment. J. Biol. Chem., 268 (6): 3829-32. [PMID:8440678]
15. Kawabe J, Iwami G, Ebina T, Ohno S, Katada T, Ueda Y, Homcy CJ, Ishikawa Y. (1994) Differential activation of adenylyl cyclase by protein kinase C isoenzymes. J. Biol. Chem., 269 (24): 16554-8. [PMID:8206971]
16. Lai HL, Lin TH, Kao YY, Lin WJ, Hwang MJ, Chern Y. (1999) The N terminus domain of type VI adenylyl cyclase mediates its inhibition by protein kinase C. Mol. Pharmacol., 56 (3): 644-50. [PMID:10462552]
17. Lustig KD, Conklin BR, Herzmark P, Taussig R, Bourne HR. (1993) Type II adenylylcyclase integrates coincident signals from Gs, Gi, and Gq. J. Biol. Chem., 268 (19): 13900-5. [PMID:8390980]
18. Onda T, Hashimoto Y, Nagai M, Kuramochi H, Saito S, Yamazaki H, Toya Y, Sakai I, Homcy CJ, Nishikawa K et al.. (2001) Type-specific regulation of adenylyl cyclase. Selective pharmacological stimulation and inhibition of adenylyl cyclase isoforms. J. Biol. Chem., 276 (51): 47785-93. [PMID:11602596]
19. Paterson JM, Smith SM, Simpson J, Grace OC, Sosunov AA, Bell JE, Antoni FA. (2000) Characterisation of human adenylyl cyclase IX reveals inhibition by Ca(2+)/Calcineurin and differential mRNA plyadenylation. J. Neurochem., 75 (4): 1358-67. [PMID:10987815]
20. Premont RT, Matsuoka I, Mattei MG, Pouille Y, Defer N, Hanoune J. (1996) Identification and characterization of a widely expressed form of adenylyl cyclase. J. Biol. Chem., 271 (23): 13900-7. [PMID:8662814]
21. Robbins JD, Boring DL, Tang WJ, Shank R, Seamon KB. (1996) Forskolin carbamates: binding and activation studies with type I adenylyl cyclase. J. Med. Chem., 39 (14): 2745-52. [PMID:8709105]
22. Sinnarajah S, Dessauer CW, Srikumar D, Chen J, Yuen J, Yilma S, Dennis JC, Morrison EE, Vodyanoy V, Kehrl JH. (2001) RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III. Nature, 409 (6823): 1051-5. [PMID:11234015]
23. Tang WJ, Krupinski J, Gilman AG. (1991) Expression and characterization of calmodulin-activated (type I) adenylylcyclase. J. Biol. Chem., 266 (13): 8595-603. [PMID:2022671]
24. Taussig R, Quarmby LM, Gilman AG. (1993) Regulation of purified type I and type II adenylylcyclases by G protein beta gamma subunits. J. Biol. Chem., 268 (1): 9-12. [PMID:8416978]
25. Taussig R, Tang WJ, Hepler JR, Gilman AG. (1994) Distinct patterns of bidirectional regulation of mammalian adenylyl cyclases. J. Biol. Chem., 269 (8): 6093-100. [PMID:8119955]
26. Tesmer JJ, Dessauer CW, Sunahara RK, Murray LD, Johnson RA, Gilman AG, Sprang SR. (2000) Molecular basis for P-site inhibition of adenylyl cyclase. Biochemistry, 39 (47): 14464-71. [PMID:11087399]
27. Watson PA, Krupinski J, Kempinski AM, Frankenfield CD. (1994) Molecular cloning and characterization of the type VII isoform of mammalian adenylyl cyclase expressed widely in mouse tissues and in S49 mouse lymphoma cells. J. Biol. Chem., 269 (46): 28893-8. [PMID:7961850]
28. Wayman GA, Impey S, Storm DR. (1995) Ca2+ inhibition of type III adenylyl cyclase in vivo. J. Biol. Chem., 270 (37): 21480-6. [PMID:7665559]
29. Yoshimura M, Cooper DM. (1992) Cloning and expression of a Ca(2+)-inhibitable adenylyl cyclase from NCB-20 cells. Proc. Natl. Acad. Sci. U.S.A., 89 (15): 6716-20. [PMID:1379717]
30. Zimmermann G, Taussig R. (1996) Protein kinase C alters the responsiveness of adenylyl cyclases to G protein alpha and betagamma subunits. J. Biol. Chem., 271 (43): 27161-6. [PMID:8900209]
How to cite this family page
Database page citation:
Adenylyl cyclases (ACs). Accessed on 18/06/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=257.
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Fabbro D, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: Enzymes. Br J Pharmacol. 174 Suppl 1: S272-S359.
Nitric oxide has been proposed to inhibit AC5 and AC6 selectively [11], although it is unclear whether this phenomenon is of physiological significance. A soluble adenylyl cyclase has been described (ADCY10, Q96PN6 [2]), unaffected by either Gα or Gβγ subunits, which has been suggested to be a cytoplasmic bicarbonate (pH-insensitive) sensor [5]. It can be inhibited selectively by KH7 (pIC50 5.0-5.5) [10].