Soluble adenylyl cyclase (sAC) and transmembrane adenylyl cyclases (tmACs) define distinct sources of cAMP 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, and because in biological systems, bicarbonate is in equilibrium with carbon dioxide (CO2) and pH, sAC could function as a physiological CO2/bicarbonate/pH chemosensor.
Our laboratory has developed genetic (i.e., knockout mice and RNAi) and pharmacological (small molecule inhibitors and activators) tools to distinguish between sAC-generated and tmAC-generated cAMP, and we are investigating whether sAC and tmAC define independent signaling cascades; i.e., whether cAMP generated by sAC performs distinct functions from cAMP generated by tmACs. Using these tools, we have thus far identified sAC as a source of cAMP within the mammalian cell nucleus and inside the matrix of mitochondria (see figure; "sAC staining in COS cells." sAC immunoreactivity in green; mitotracker in red; nucleus in blue). We have also determined that mammalian sAC 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 (and possibly the kidney); (3) CO2 induced ciliary beating in lung epithelia; (4) Bicarbonate dependent regulation of aqueous humor flow in the eye; and (5) metabolic sensing in a variety of tissues.