Intracellular cAMP signaling by soluble adenylyl cyclase

Tresguerres, Martín; Levin, Lonny R.; Buck, Jochen

doi:10.1038/ki.2011.95

Cited by 183 publications

(204 citation statements)

References 158 publications

(222 reference statements)

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“…Adcy10 was origi-nally thought to be restricted to testis and sperm (9), but more recently it has been identified in other cell types (reviewed in Ref. 10). In contrast to tmACs, Adcy10 is insensitive to either heterotrimeric G proteins or the natural bicyclic diterpene forskolin (FK); instead, it is regulated by HCO 3 Ϫ and Ca 2ϩ ions (8,11,12).…”

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confidence: 99%

Compartmentalization of Distinct cAMP Signaling Pathways in Mammalian Sperm

Wertheimer

Krapf

Vega-Beltrán

et al. 2013

Journal of Biological Chemistry

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Background: cAMP is essential for the acquisition of sperm fertilizing capacity. The presence of transmembrane adenylyl cyclases (tmACs) in sperm remains controversial. Results: tmAC activity and its activator G s are detected in the sperm head. Conclusion: Two cAMP synthesis pathways coexist in sperm and lead to capacitation. Significance: Understanding capacitation is essential for improvement of assisted fertilization and for finding novel contraceptive targets.

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confidence: 99%

Compartmentalization of Distinct cAMP Signaling Pathways in Mammalian Sperm

Wertheimer

Krapf

Vega-Beltrán

et al. 2013

Journal of Biological Chemistry

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“…Via modulation of sAC, and sAClike cyclase activities, HCO 3 − serves as an evolutionarily conserved signaling molecule mediating cellular responses to HCO 3 − , CO 2 , and pH (3,14). 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).…”

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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.

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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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“…This would result in an increase in aqueous flow as observed, but would not explain the effects observed on drainage in Best2 Ϫ/Ϫ mice. Soluble adenylyl cyclase (sAC) serves as a HCO 3 Ϫ sensor in many tissues (14,15). sAC catalyzes the formation of cAMP in response to increasing HCO 3 Ϫ .…”

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confidence: 99%

Regulation of Anterior Chamber Drainage by Bicarbonate-sensitive Soluble Adenylyl Cyclase in the Ciliary Body

Yong-Suk

Tresguerres

Hess

et al. 2011

Journal of Biological Chemistry

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Glaucoma is a leading cause of blindness affecting as many as 2.2 million Americans. All current glaucoma treatment strategies aim to reduce intraocular pressure (IOP). IOP results from the resistance to drainage of aqueous humor (AH) produced by the ciliary body in a process requiring bicarbonate. Once secreted into the anterior chamber, AH drains from the eye via two pathways: uveoscleral and pressure-dependent or conventional outflow (C t ). Modulation of "inflow" and "outflow" pathways is thought to occur via distinct, local mechanisms. Mice deficient in the bicarbonate channel bestrophin-2 (Best2), however, exhibit a lower IOP despite an increase in AH production. Best2 is expressed uniquely in nonpigmented ciliary epithelial (NPE) cells providing evidence for a bicarbonate-dependent communicative pathway linking inflow and outflow. Here, we show that bicarbonate-sensitive soluble adenylyl cyclase (sAC) is highly expressed in the ciliary body in NPE cells, but appears to be absent from drainage tissues. Pharmacologic inhibition of sAC in mice causes a significant increase in IOP due to a decrease in C t with no effect on inflow. In mice deficient in sAC IOP is elevated, and C t is decreased relative to wild-type mice. Pharmacologic inhibition of sAC did not alter IOP or C t in sACdeficient mice. Based on these data we propose that the ciliary body can regulate C t and that sAC serves as a critical sensor of bicarbonate in the ciliary body regulating the secretion of substances into the AH that govern outflow facility independent of pressure.

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Intracellular cAMP signaling by soluble adenylyl cyclase

Cited by 183 publications

References 158 publications

Compartmentalization of Distinct cAMP Signaling Pathways in Mammalian Sperm

Compartmentalization of Distinct cAMP Signaling Pathways in Mammalian Sperm

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

Regulation of Anterior Chamber Drainage by Bicarbonate-sensitive Soluble Adenylyl Cyclase in the Ciliary Body

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