Bicarbonate-sensing soluble adenylyl cyclase is an essential sensor for acid/base homeostasis

pH homeostasis is essential for life, yet it remains unclear how animals sense their systemic acid/base (A/B) status. Soluble adenylyl cyclase (sAC) is an evolutionary conserved signaling enzyme that produces the second messenger cAMP in response to bicarbonate ions (HC[O.sub.3.sup.-]). We cloned the sAC ortholog from the dogfish, a shark that regulates blood A/B by absorbing and secreting protons ([H.sup.+]) and HC[O.sub.3.sup.-] at its gills. Similar to mammalian sAC, dogfish soluble adenylyl cyclase (dfsAC) is activated by HC[O.sub.3.sup.-] and can be inhibited by two structurally and mechanistically distinct small molecule inhibitors, dfsAC is expressed in the gill epithelium, where the subset of base-secreting cells resides. Injection of inhibitors into animals under alkaline stress confirmed that dfsAC is essential for maintaining systemic pH and HC[O.sub.3.sup.-] levels in the whole organism. One of the downstream effects of dfsAC is to promote the insertion of vacuolar proton pumps into the basolateral membrane to absorb [H.sup.+] into the blood, sAC orthologs are present throughout metazoans, and mammalian sAC is expressed in A/B regulatory organs, suggesting that systemic A/B sensing via sAC is widespread in the animal kingdom. cAMP | pH | proton pump | dogfish | gill www.pnas.org/cgi/doi/10.1073/pnas.0911790107