Capturing adenylyl cyclases as potential drug targets

Pierre, Sandra; Eschenhagen, Thomas; Geißlinger, Gerd; Scholich, Klaus

doi:10.1038/nrd2827

Cited by 202 publications

(244 citation statements)

References 164 publications

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“…Pharmacological sAC modulation has potential therapeutic applications (19)(20)(21)39), and because artificially manipulating the natural activator bicarbonate is problematic in physiological systems, sAC-selective modulators would facilitate in vivo studies. In tmAC, the space corresponding to the hydrophilic sAC BBS between Arg176 (Asn in tmAC) and Lys95 is blocked by a hydrophobic residue (Leu438 in tmACV-C 1 , interacting with Phe338).…”

Section: Resultsmentioning

confidence: 99%

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Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Kleinboelting

Díaz

Moniot

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

215

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cAMP is an evolutionary conserved, prototypic second messenger regulating numerous cellular functions. In mammals, cAMP is synthesized by one of 10 homologous adenylyl cyclases (ACs): nine transmembrane enzymes and one soluble AC (sAC). Among these, only sAC is directly activated by bicarbonate (HCO3−); it thereby serves as a cellular sensor for HCO3−, carbon dioxide (CO2), and pH in physiological functions, such as sperm activation, aqueous humor formation, and metabolic regulation. Here, we describe crystal structures of human sAC catalytic domains in the apo state and in complex with substrate analog, products, and regulators. The activator HCO3− binds adjacent to Arg176, which acts as a switch that enables formation of the catalytic cation sites. An anionic inhibitor, 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid, inhibits sAC through binding to the active site entrance, which blocks HCO3− activation through steric hindrance and trapping of the Arg176 side chain. Finally, product complexes reveal small, local rearrangements that facilitate catalysis. Our results provide a molecular mechanism for sAC catalysis and cellular HCO3− sensing and a basis for targeting this system with drugs.

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Section: Resultsmentioning

confidence: 99%

“…In mammals, sAC acts as a CO 2 /HCO 3 − /pH sensor in processes such as sperm activation (15), acid-base homeostasis (16), and various metabolic responses (10,17,18). sAC has also been implicated in skin and prostate cancer and as a target for male contraceptives (19)(20)(21).…”

mentioning

confidence: 99%

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Kleinboelting

Díaz

Moniot

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

123

215

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“…By contrast, adenosine-derived cAMP signaling can attenuate many of these effects (5). Moreover, cAMP produced by different adenylyl cyclases (ACs) has different cardiac effects: AC5-derived cAMP is detrimental, whereas AC6-derived cAMP is protective in pathological cardiac remodeling (6). cGMP is generated from both the soluble and particulate guanylyl cyclases (GCs), and many studies have shown negative inotropic and cardioprotective effects (7,8) from cardiac cGMP signaling.…”

mentioning

confidence: 99%

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

Knight

Chen

Zhang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β-stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.cyclic nucleotide | phosphodiesterase | cardiac remodeling | heart failure

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“…8 To begin to evaluate the role of individual AC isoforms in PKD renal disease, we have now studied mouse models of polycystin-1 deficiency with or without AC6 deficiency. Given that no specific AC isoform inhibitors exist (although this area represents an active area of drug development 9 ), a genetic engineering approach was used. We previously reported a mouse model of PKD by selectively deleting the Pkd1 gene in CD principal cells.…”

mentioning

confidence: 99%

Adenylyl Cyclase 6 Deficiency Ameliorates Polycystic Kidney Disease

Rees

Kittikulsuth

Roos

et al. 2014

Journal of the American Society of Nephrology

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ABSTRACTcAMP is an important mediator of cystogenesis in polycystic kidney disease (PKD). Several adenylyl cyclase (AC) isoforms could mediate cAMP accumulation in PKD, and identification of a specific pathogenic AC isoform is of therapeutic interest. We investigated the role of AC6 in a mouse model of PKD that is homozygous for the loxP-flanked PKD1 gene and heterozygous for an aquaporin-2-Cre recombinase transgene to achieve collecting duct-specific gene targeting. Collecting duct-specific knockout of polycystin-1 caused massive renal cyst formation, kidney enlargement, and severe kidney failure, with a mean survival time of 2 months. In contrast, coincident collecting duct-specific knockout of polycystin-1 and AC6 (also homozygous for the floxed ADCY6 gene) markedly decreased kidney size and cystogenesis, improved renal function, reduced activation of the B-Raf/ERK/MEK pathway, and greatly increased survival. Absence of collecting duct AC6 did not alter urinary cAMP excretion or kidney cAMP concentration. In conclusion, AC6 is a key mediator of cyst formation and renal injury in a model of PKD.

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Capturing adenylyl cyclases as potential drug targets

Cited by 202 publications

References 164 publications

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

Adenylyl Cyclase 6 Deficiency Ameliorates Polycystic Kidney Disease

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