Soluble adenylyl cyclase and carbon dioxide sensing via cAMP
The second messenger molecule cAMP, which modulates cell growth and differentiation in organisms from bacteria to higher eukaryotes, is produced by adenylyl cyclases. Mammals possess two distinct classes of adenylyl cyclase, the hormone-responsive, transmembrane adenylyl cyclases (tmAC) and the bicarbonate-regulated Soluble Adenylyl Cyclase (sAC). We purified and cloned sAC, and it is now studied in our combined laboratory. Despite its more recent discovery, sAC represents the primordial cyclase in mammals. In contrast to tmACs, which are modulated by heterotrimeric G proteins in response to extracellular signals acting through seven-transmembrane spanning, G protein-coupled receptors, sAC is directly regulated by intracellular signals such as bicarbonate and calcium ions.
In eukaryotic cells, second messengers, such as cAMP, can play multiple, disparate roles within in a single cell. This is achieved by compartmentalization into independently regulated signaling microdomains distributed throughout the cell. For example, in a single cell, sAC-generated cAMP modulates distinct effectors from tmAC-generated cAMP. We have shown sAC is distributed to intracellular sites containing cAMP effectors; therefore, it seems to represent the source of second messenger for intracellular cAMP signaling microdomains.
In mammals, sAC also plays tissue-specific functions. Our work has shown sAC to be the source of cAMP responsible for (1) a number of bicarbonate-induced, cAMP-dependent processes required for sperm to fertilize an egg; (2) pH dependent proton secretion in the epididymis; (3) responses to inflammatory signals in neutrophil; (4) responses to neurotrophins and guidance cues in neurons; and (5) sensing nutritional availability. Additionally, as the only identified bicarbonate/carbon dioxide chemosensor in mammals, sAC may also be involved in fluid reabsorption in the kidney, fluid secretion in the ciliary bodies and choroid plexus, and metabolic regulation in response to nutritional signals. Metabolic pathways resulting in energy generation also produce carbon dioxide as by-product. Because sAC is directly modulated by bicarbonate, which will be in an instantaneous equilibrium with carbon dioxide due to the ubiquitous presence of carbonic anhydrases, sAC is poised to respond to changes in carbon dioxide production and sense the metabolic state of the cell. Cancer cells, which are known to have higher metabolically activities than wild type cells, must increase their metabolic rates. Because it is known that cAMP and PKA modulate metabolic processes such as glycolysis and the electron transport chain, we are investigating whether sAC is involved in the increased metabolic rate found in cancer cells. We are currently testing these hypothesized physiological functions pharmacologically and genetically using RNAi and by making inducible, tissue-specific knockouts of the sAC gene in mice.
Bicarbonate regulated cyclases are evolutionarily conserved from unicellular bacteria to man. We also study the role of CO2/bicarbonate regulation of cAMP signaling in medically relevant micro-organisms. Our data suggest that bicarbonate regulation of cAMP synthesis serves as nature’s carbon dioxide chemosensor.
Keywords:
Adenylyl cyclase, cAMP, second messengers, signal transduction, compartmentalization, metabolic sensing, bicarbonate
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