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). sAC, which we purified and cloned in collaboration with Dr. Jochen Buck's Laboratory, and tmACs define distinct cAMP signaling pathways within eukaryotic cells. tmACs are modulated by heterotrimeric G proteins in response to extracellular signals acting through seven-transmembrane spanning, G protein-coupled receptors. In contrast, sAC is directly regulated by bicarbonate ions suggesting it functions as the physiological carbon dioxide chemosensor. sAC most closely resembles cyanobacterial adenylyl cyclases, and regulation by bicarbonate ions is also conserved in these cyclases from blue-green algae. Therefore, sAC may represent the primordial cyclase in mammals.

In recent years, it has become increasing clear that cAMP signaling pathways are compartmentalized throughout the cell. Different effectors of cAMP have distinct subcellular localizations which appear to operate as independently controlled microdomains. Within cellular contexts, sAC is the only known adenylyl cyclase not tethered to the plasma membrane suggesting it repersents the source of second messenger for intracellular microdomains.

Mammalian sAC also plays a number of tissue-specific functions. Thus far, our studies have revealed sAC to be the source of cAMP mediating; (1) the series of bicarbonate-induced, cAMP-dependent processes required for sperm to fertilize an egg; (2) pH induced proton secretion in the epididymis; (3) the cAMP dependent processes in neurons elicited by neurotrophins and guidance cues; and (4) metabolic sensing. 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. We are currently testing these hypothesized physiological functions pharmacologically and genetically, through the use of RNAi and by generating inducible, tissue-specific knockouts of the sAC gene in mice.

sAC-like adenylyl cyclases are evolutionarily conserved from unicellular organisms to man, and we also studying the role of CO₂ and bicarbonate sensing via modulation of the cAMP pathway in a number of medically relevant micro-organisms.


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