Soluble adenylyl cyclase as an evolutionarily conserved bicarbonate sensor

Spermatozoa undergo a poorly understood activation process induced by bicar bonate and mediated by cyclic adenosine 3',5'-monophosphate (cAMP). It has been assumed that bicarbonate mediates its effects through changes in intra cellular pH or membrane potential; however, we demonstrate here that bicarb onate directly stimulates mammalian soluble adenylyl cyclase (sAC) activity in vivo and in vitro in a pH-independent manner. sAC is most similar to ad enylyl cyclases from cyanobacteria, and bicarbonate regulation of cyclase a ctivity is conserved in these early forms of life. sAC is also expressed in other bicarbonate-responsive tissues, which suggests that bicarbonate regu lation of cAMP signaling plays a fundamental role in many biological system s.