title: Bicarbonate-sensing soluble adenylyl cyclase is an essential sensor for acid/base homeostasis.
abstract: 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 (HCO(3)(-)). We cloned the sAC ortholog from the dogfish, a shark that regulates blood A/B by absorbing and secreting protons (H(+)) and HCO(3)(-) at its gills. Similar to mammalian sAC, dogfish soluble adenylyl cyclase (dfsAC) is activated by HCO(3)(-) 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 HCO(3)(-) 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(+) 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.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA. mat2031@med.cornell.edu
authors.forename: Martin
authors.initials: M
authors.lastname: Tresguerres
authors.forename: Scott K
authors.initials: SK
authors.lastname: Parks
authors.forename: Eric
authors.initials: E
authors.lastname: Salazar
authors.forename: Lonny R
authors.initials: LR
authors.lastname: Levin
authors.forename: Greg G
authors.initials: GG
authors.lastname: Goss
authors.forename: Jochen
authors.initials: J
authors.lastname: Buck
mesh_terms: D000136:Acid-Base Equilibrium / Q000502:physiology*; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D000471:Alkalosis / Q000378:metabolism; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism*; D004284:Dogfish; D005880:Gills / Q000201:enzymology; D006706:Homeostasis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D010802:Phylogeny
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D001639:Bicarbonates; D000262:Adenylyl Cyclases