Water absorption and bicarbonate secretion in the intestine of the sea bream are regulated by transmembrane and soluble adenylyl cyclase stimulation

Background: Primary biliary cholangitis (PBC; previously referred to as primary biliary cirrhosis) is a chronic fibrosing cholangiopathy with the signature of an autoimmune disease and features of intrahepatic cholestasis. Immunosuppressing treatments are largely unsuccessful. Responsiveness to ursodeoxycholic acid and reduced expression of anion exchanger 2 (AE2) on canalicular membranes and small bile ducts underline the importance of bicarbonate transportation in its disease mechanism. Soluble adenylyl cyclase (sAC; ADCY10) is an evolutionarily conserved bicarbonate sensor that regulates apoptosis, barrier function and TNF signaling. Key Messages: The biliary epithelium defends against the toxic bile by bicarbonate secretion and by maintaining a tight barrier. Passive diffusion of weak acid conjugates (e.g. bile salts and other toxins) across plasma membrane is pH-dependent. Reduced AE2 expression results in both reduced bicarbonate secretion and accumulation of bicarbonate in the cells. Increased intracellular bicarbonate leads to increased sAC activity, which regulates bile salt-induced apoptosis. Reduced bicarbonate secretion causes more bile salts to enter cells, which further increase sAC activity by releasing intracellular Ca2+ store. In vitro studies demonstrate that inhibition of sAC not only corrects sensitization to bile salt-induced apoptosis as a result of AE2 down-regulation but also prevents bile salt-induced apoptosis altogether. Targeting sAC is also likely to slow down disease progression by strengthening the barrier function of biliary epithelia and by reducing oxidative stress as a result of chronic inflammation. Conclusions: sAC is a potential therapeutic target for PBC. More in vitro and in vivo studies are needed to understand how sAC regulates bile salt-induced apoptosis and to establish its therapeutic value in PBC and other cholestatic cholangiopathies.

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Faculty Opinions recommendation of Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1440961.919059 ◽

2010 ◽

Author(s):

Eduardo Rial

Keyword(s):

Protein Phosphorylation ◽

Adenylyl Cyclase ◽

Cytochrome Oxidase ◽

Mitochondrial Protein ◽

Soluble Adenylyl Cyclase

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Faculty Opinions recommendation of Endothelial CD99 signals through soluble adenylyl cyclase and PKA to regulate leukocyte transendothelial migration.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725582304.793522829 ◽

2016 ◽

Author(s):

Dietmar Vestweber

Keyword(s):

Adenylyl Cyclase ◽

Transendothelial Migration ◽

Soluble Adenylyl Cyclase ◽

Leukocyte Transendothelial Migration

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Two domains are critical for the nuclear localization of soluble adenylyl cyclase

Biochimie ◽

10.1016/j.biochi.2005.09.003 ◽

2006 ◽

Vol 88 (3-4) ◽

pp. 319-328 ◽

Cited By ~ 19

Author(s):

Q FENG ◽

Y ZHANG ◽

Y LI ◽

Z LIU ◽

J ZUO ◽

...

Keyword(s):

Adenylyl Cyclase ◽

Nuclear Localization ◽

Soluble Adenylyl Cyclase

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Non-canonical regulation of glycogenolysis and the Warburg phenotype by soluble adenylyl cyclase

10.1101/2020.02.02.929901 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jung-Chin Chang ◽

Simei Go ◽

Eduardo H. Gilglioni ◽

Hang Lam Li ◽

Hsu-Li Huang ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Adenylyl Cyclase ◽

Energy Homeostasis ◽

Aerobic Glycolysis ◽

Glycogen Metabolism ◽

Adenylyl Cyclases ◽

Soluble Adenylyl Cyclase ◽

Atp Level ◽

Downstream Effectors ◽

Different Types

AbstractCyclic AMP is produced in cells by two very different types of adenylyl cyclases: the canonical transmembrane adenylyl cyclases (tmACs, ADCY1∼9) and the evolutionarily more conserved soluble adenylyl cyclase (sAC, ADCY10). While the role and regulation of tmACs is well documented, much less is known of sAC in cellular metabolism. We demonstrate here that sAC is an acute regulator of glycolysis, oxidative phosphorylation and glycogen metabolism, tuning their relative bioenergetic contributions. Suppression of sAC activity leads to aerobic glycolysis, enhanced glycogenolysis, decreased oxidative phosphorylation, and an elevated cytosolic NADH/NAD+ ratio, resembling the Warburg phenotype. Importantly, we found that glycogen metabolism is regulated in opposite directions by cAMP depending on its location of synthesis and downstream effectors. While the canonical tmAC-cAMP-PKA axis promotes glycogenolysis, we identify a novel sAC-cAMP-Epac1 axis that suppresses glycogenolysis. These data suggest that sAC is an autonomous bioenergetic sensor that suppresses aerobic glycolysis and glycogenolysis when ATP levels suffice. When the ATP level falls, diminished sAC activity induces glycogenolysis and aerobic glycolysis to maintain energy homeostasis.

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Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization

10.1101/2021.04.27.441671 ◽

2021 ◽

Author(s):

Melanie Balbach ◽

Lubna Ghanem ◽

Thomas Rossetti ◽

Navpreet Kaur ◽

Carla Ritagliati ◽

...

Keyword(s):

Adenylyl Cyclase ◽

Acrosome Reaction ◽

Human Sperm ◽

Comprehensive Analysis ◽

Multiple Points ◽

Soluble Adenylyl Cyclase ◽

Mouse Sperm ◽

On Demand ◽

Sperm Functions

AbstractSoluble adenylyl cyclase (sAC: ADCY10) is essential for activating dormant sperm. Studies of freshly dissected mouse sperm identified sAC as needed for initiating capacitation and activating motility. We now use an improved sAC inhibitor, TDI-10229, for a comprehensive analysis of sAC function in human sperm. Unlike dissected mouse sperm, human sperm are collected post-ejaculation, after sAC activity has already been stimulated. Even in ejaculated human sperm, TDI-10229 interrupts stimulated motility and capacitation, and it prevents acrosome reaction in capacitated sperm. At present, there are no non-hormonal, pharmacological methods for contraception. Because sAC activity is required post-ejaculation at multiple points during the sperm’s journey to fertilize the oocyte, sAC inhibitors define candidates for non-hormonal, on-demand contraceptives suitable for delivery via intravaginal devices in females.

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