scholarly journals External fertilization is orchestrated by a pH-regulated soluble adenylyl cyclase controlling sperm motility and chemotaxis

2021 ◽  
Author(s):  
Heinz Gerd Koerschen ◽  
Hussein Hamzeh ◽  
Rene Pascal ◽  
Luis Alvarez ◽  
Wolfgang Boenigk ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Ph Control ◽  
Evolutionary Significance ◽  
Hcn Channels ◽  
Ph Sensing ◽  
Amino Acid Residues ◽  
External Fertilization ◽  
Soluble Adenylyl Cyclase ◽  
Camp Synthesis ◽  
Mammalian Sperm

The reaction of CO2 with H2O to form HCO3- and H+ is one of the most important chemical equilibria in cells. In mammalian sperm, a soluble adenylyl cyclase (sAC) serves as cellular HCO3- sensor that conveys the equilibrium state via cAMP synthesis to cAMP-signaling molecules. The function of sAC and cAMP in non-mammalian sperm is largely unknown. Here, we identify sAC orthologs in sea urchin and salmon sperm that, surprisingly, are activated by alkaline pH rather than HCO3-. Two amino-acid residues required for HCO3- binding of mammalian sAC are lacking in pH-regulated sAC. Orthologs identified in ten other phyla are also lacking either one of these key residues, suggesting that pH control is widespread among non-mammalian metazoan. The pH-sensitive sAC controls several functions of sperm from external fertilizers. Upon spawning, alkalization triggers cAMP synthesis and, thereby, activates motility of quiescent sperm. Egg-derived chemoattractants also alkalize sperm and elevate cAMP, which then-modulates pacemaker HCN channels to trigger a chemotactic Ca2+ response. Finally, the sAC and the voltage- and cAMP-activated Na+/H+ exchanger sNHE mutually control each other. A picture of evolutionary significance is emerging: motility and sensory signaling of sperm from both internal and external fertilizers rely on cAMP, yet, their sAC is regulated by HCO3- or pHi, respectively. Acidification of aquatic habitats due to climate change may adversely affect pH-sensing by sAC and thereby sexual reproduction in the sea.

Bicarbonate, carbon dioxide and pH sensing via mammalian bicarbonate-regulated soluble adenylyl cyclase

2021 ◽  
Vol 11 (2) ◽  
pp. 20200034
Author(s):  
Tom Rossetti ◽  
Stephanie Jackvony ◽  
Jochen Buck ◽  
Lonny R. Levin
Keyword(s):  
Carbon Dioxide ◽  
Adenylyl Cyclase ◽  
Ph Sensor ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Signalling Pathways ◽  
Ph Sensing ◽  
Carbonic Anhydrases ◽  
Soluble Adenylyl Cyclase ◽  
Ubiquitous Presence

Soluble adenylyl cyclase (sAC; ADCY10) is a bicarbonate (HCO 3 − )-regulated enzyme responsible for the generation of cyclic adenosine monophosphate (cAMP). sAC is distributed throughout the cell and within organelles and, as such, plays a role in numerous cellular signalling pathways. Carbonic anhydrases (CAs) nearly instantaneously equilibrate HCO 3 − , protons and carbon dioxide (CO 2 ); because of the ubiquitous presence of CAs within cells, HCO 3 − -regulated sAC can respond to changes in any of these factors. Thus, sAC can function as a physiological HCO 3 − /CO 2 /pH sensor. Here, we outline examples where we have shown that sAC responds to changes in HCO 3 − , CO 2 or pH to regulate diverse physiological functions.

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

Biochimie ◽  
2006 ◽  
Vol 88 (3-4) ◽  
pp. 319-328 ◽  
Author(s):  
Q FENG ◽  
Y ZHANG ◽  
Y LI ◽  
Z LIU ◽  
J ZUO ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Nuclear Localization ◽  
Soluble Adenylyl Cyclase

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

2020 ◽  
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.

scholarly journals Pharmacological and genetic activation of cAMP synthesis disrupts cholesterol utilization in Mycobacterium tuberculosis

2021 ◽  
Author(s):  
Kaley M. Wilburn ◽  
Christine R. Montague ◽  
Bo Qin ◽  
Ashley K. Woods ◽  
Melissa S. Love ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Adenylyl Cyclase ◽  
Cholesterol Metabolism ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Signaling ◽  
Camp Synthesis ◽  
Pharmacokinetic Properties ◽  
Bacterial Utilization

There is a growing appreciation for the idea that bacterial utilization of host-derived lipids, including cholesterol, supports Mycobacterium tuberculosis (Mtb) pathogenesis. This has generated interest in identifying novel antibiotics that can disrupt cholesterol utilization by Mtb in vivo. Here we identify a novel small molecule agonist (V-59) of the Mtb adenylyl cyclase Rv1625c, which stimulates 3’, 5’-cyclic adenosine monophosphate (cAMP) synthesis and inhibits cholesterol utilization by Mtb. Similarly, using a complementary genetic approach that induces bacterial cAMP synthesis independent of Rv1625c, we demonstrate that inducing cAMP synthesis is sufficient to inhibit cholesterol utilization in Mtb. Although the physiological roles of individual adenylyl cyclase enzymes in Mtb are largely unknown, here we demonstrate that the transmembrane region of Rv1625c is required for cholesterol metabolism. Finally, in this work the pharmacokinetic properties of Rv1625c agonists are optimized, producing an orally-available Rv1625c agonist that impairs Mtb pathogenesis in infected mice. Collectively, this work demonstrates a novel role for Rv1625c and cAMP signaling in controlling cholesterol metabolism in Mtb and establishes that cAMP signaling can be pharmacologically manipulated for the development of new antibiotic strategies.

scholarly journals Soluble adenylyl cyclase inhibition prevents human sperm functions essential for fertilization

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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