Role of the bicarbonate-responsive soluble adenylyl cyclase in cholangiocyte apoptosis in primary biliary cholangitis; a new hypothesis

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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The role of soluble adenylyl cyclase in RAF regulation

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2014.01.139 ◽

2014 ◽

Vol 70 (5) ◽

pp. AB33

Keyword(s):

Adenylyl Cyclase ◽

Soluble Adenylyl Cyclase

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cAMP and Mitochondria

Physiology ◽

10.1152/physiol.00004.2013 ◽

2013 ◽

Vol 28 (3) ◽

pp. 199-209 ◽

Cited By ~ 79

Author(s):

Federica Valsecchi ◽

Lavoisier S. Ramos-Espiritu ◽

Jochen Buck ◽

Lonny R. Levin ◽

Giovanni Manfredi

Keyword(s):

Protein Phosphorylation ◽

Adenylyl Cyclase ◽

Regulatory Mechanism ◽

Mitochondrial Proteins ◽

Camp Signaling ◽

Metabolic Adaptation ◽

Mitochondrial Bioenergetics ◽

Soluble Adenylyl Cyclase

Phosphorylation of mitochondrial proteins has emerged as a major regulatory mechanism for metabolic adaptation. cAMP signaling and PKA phosphorylation of mitochondrial proteins have just started to be investigated, and the presence of cAMP-generating enzymes and PKA inside mitochondria is still controversial. Here, we discuss the role of cAMP in regulating mitochondrial bioenergetics through protein phosphorylation and the evidence for soluble adenylyl cyclase as the source of cAMP inside mitochondria.

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Protective role of soluble adenylyl cyclase against reperfusion-induced injury of cardiac cells

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2018.07.021 ◽

2019 ◽

Vol 1865 (1) ◽

pp. 252-260 ◽

Cited By ~ 3

Author(s):

Laura Rinaldi ◽

Sofya Pozdniakova ◽

Vignesh Jayarajan ◽

Christian Troidl ◽

Yaser Abdallah ◽

...

Keyword(s):

Adenylyl Cyclase ◽

Protective Role ◽

Cardiac Cells ◽

Soluble Adenylyl Cyclase

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The role of soluble adenylyl cyclase in neurite outgrowth

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2014.07.012 ◽

2014 ◽

Vol 1842 (12) ◽

pp. 2561-2568 ◽

Cited By ~ 11

Author(s):

Travis L. Stiles ◽

Michael S. Kapiloff ◽

Jeffrey L. Goldberg

Keyword(s):

Adenylyl Cyclase ◽

Neurite Outgrowth ◽

Soluble Adenylyl Cyclase

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Effect of Soluble Adenylyl Cyclase (ADCY10) Inhibitors on the LH-Stimulated cAMP Synthesis in Mltc-1 Leydig Cell Line

International Journal of Molecular Sciences ◽

10.3390/ijms22094641 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4641

Author(s):

Thi Mong Diep Nguyen ◽

Laura Filliatreau ◽

Danièle Klett ◽

Nong Van Hai ◽

Nguyen Thuy Duong ◽

...

Keyword(s):

Adenylyl Cyclase ◽

Leydig Cells ◽

Intracellular Camp ◽

Camp Accumulation ◽

Adenylyl Cyclases ◽

High Concentration ◽

Soluble Adenylyl Cyclase ◽

Bicarbonate Ions ◽

Intracellular Camp Accumulation

In contrast to all transmembrane adenylyl cyclases except ADCY9, the cytosolic soluble adenylyl cyclase (ADCY10) is insensitive to forskolin stimulation and is uniquely modulated by calcium and bicarbonate ions. In the present paper, we focus on ADCY10 localization and a kinetic analysis of intracellular cAMP accumulation in response to human LH in the absence or presence of four different ADCY10 inhibitors (KH7, LRE1, 2-CE and 4-CE) in MTLC-1 cells. ADCY10 was immuno-detected in the cytoplasm of MLTC-1 cells and all four inhibitors were found to inhibit LH-stimulated cAMP accumulation and progesterone level in MLTC-1 and testosterone level primary Leydig cells. Interestingly, similar inhibitions were also evidenced in mouse testicular Leydig cells. In contrast, the tmAC-specific inhibitors ddAdo3′ and ddAdo5′, even at high concentration, exerted weak or no inhibition on cAMP accumulation, suggesting an important role of ADCY10 relative to tmACs in the MLTC-1 response to LH. The strong synergistic effect of HCO3− under LH stimulation further supports the involvement of ADCY10 in the response to LH.

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