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Pharmacol Rev. 2017 Apr;69(2):93-139. doi: 10.1124/pr.116.013078.

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases.

Author information

1
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Sciences Center at Houston, Houston, Texas (C.W.D.); Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (V.J.W.); Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California (R.S.O.); Center for Reproductive Sciences, University of California San Francisco, San Francisco, California (M.C.); Institute of Pharmacy, University of Regensburg, Regensburg, Germany (S.D.); and Institute of Pharmacology, Hannover Medical School, Hannover, Germany (R.S.) Carmen.W.Dessauer@uth.mc.edu.
2
Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Sciences Center at Houston, Houston, Texas (C.W.D.); Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana (V.J.W.); Department of Biomedical and Pharmaceutical Sciences, Chapman University School of Pharmacy, Irvine, California (R.S.O.); Center for Reproductive Sciences, University of California San Francisco, San Francisco, California (M.C.); Institute of Pharmacy, University of Regensburg, Regensburg, Germany (S.D.); and Institute of Pharmacology, Hannover Medical School, Hannover, Germany (R.S.).

Abstract

Adenylyl cyclases (ACs) generate the second messenger cAMP from ATP. Mammalian cells express nine transmembrane AC (mAC) isoforms (AC1-9) and a soluble AC (sAC, also referred to as AC10). This review will largely focus on mACs. mACs are activated by the G-protein Gαs and regulated by multiple mechanisms. mACs are differentially expressed in tissues and regulate numerous and diverse cell functions. mACs localize in distinct membrane compartments and form signaling complexes. sAC is activated by bicarbonate with physiologic roles first described in testis. Crystal structures of the catalytic core of a hybrid mAC and sAC are available. These structures provide detailed insights into the catalytic mechanism and constitute the basis for the development of isoform-selective activators and inhibitors. Although potent competitive and noncompetitive mAC inhibitors are available, it is challenging to obtain compounds with high isoform selectivity due to the conservation of the catalytic core. Accordingly, caution must be exerted with the interpretation of intact-cell studies. The development of isoform-selective activators, the plant diterpene forskolin being the starting compound, has been equally challenging. There is no known endogenous ligand for the forskolin binding site. Recently, development of selective sAC inhibitors was reported. An emerging field is the association of AC gene polymorphisms with human diseases. For example, mutations in the AC5 gene (ADCY5) cause hyperkinetic extrapyramidal motor disorders. Overall, in contrast to the guanylyl cyclase field, our understanding of the (patho)physiology of AC isoforms and the development of clinically useful drugs targeting ACs is still in its infancy.

PMID:
28255005
PMCID:
PMC5394921
DOI:
10.1124/pr.116.013078
[Indexed for MEDLINE]
Free PMC Article

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