Dessauer, Carmen W. and Watts, Val J. and Ostrom, Rennolds S. and Conti, Marco and Dove, Stefan and Seifert, Roland (2017) International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases. PHARMACOLOGICAL REVIEWS, 69 (2). pp. 93-139. ISSN 0031-6997, 1521-0081
Full text not available from this repository. (Request a copy)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 G alpha(s) 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 isoformselective activators and inhibitors. Although potent competitive and noncompetitive mAC inhibitors are available, it is challenging to obtain compoundswith 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BETA-GAMMA-SUBUNITS; PROTEIN-KINASE-A; SOLUBLE GUANYLYL CYCLASE; LEFT-VENTRICULAR FUNCTION; GENOME-WIDE ASSOCIATION; CAPACITATIVE CA2+ ENTRY; AIRWAY SMOOTH-MUSCLE; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; GENOTYPE-PHENOTYPE CORRELATIONS; BINDING REGULATORY COMPONENT; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Petra Gürster |
| Date Deposited: | 14 Dec 2018 13:00 |
| Last Modified: | 04 Sep 2020 06:41 |
| URI: | https://pred.uni-regensburg.de/id/eprint/185 |
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