Role of the bicarbonate-responsive soluble adenylyl cyclase in pH sensing and metabolic regulation

Abstract

The evolutionarily conserved soluble adenylyl cyclase (sAC, adcy10) was recently identified as a unique source of cAMP in the cytoplasm and the nucleus. Its activity is regulated by bicarbonate and fine-tuned by calcium. As such, and in conjunction with carbonic anhydrase (CA), sAC constitutes an HCO−3/CO−2/pH sensor. In both alpha-intercalated cells of the collecting duct and the clear cells of the epididymis, sAC is expressed at significant level and involved in pH homeostasis via apical recruitment of vacuolar H+-ATPase (VHA) in a PKA-dependent manner. In addition to maintenance of pH homeostasis, sAC is also involved in metabolic regulation such as coupling of Krebs cycle to oxidative phosphorylation via bicarbonate/CO2 sensing. Additionally, sAC also regulates CFTR channel and plays an important role in regulation of barrier function and apoptosis. These observations suggest that sAC, via bicarbonate-sensing, plays an important role in maintaining homeostatic status of cells against fluctuations in their microenvironment.

Global Role of Cyclic AMP Signaling in pH-Dependent Responses in Candida albicans

“…pH has been postulated to regulate bicarbonate-sensitive adenylate cyclases in a number of systems (development of mammalian spermatozoa during capacitation being the classic example), but to our knowledge, the extent of perturbation of pH i necessary to alter adenylate cyclase output has not been empirically determined in vivo (46–48). We observed a shift in strain SC5314 from pH i  8.0 to pH i  6.6 between neutral and acidic culture conditions, and it is plausible that this represents a significant change in the bicarbonate/carbonic acid equilibrium and Cyr1 activation.…”

The metabolic/pH sensor soluble adenylyl cyclase is a tumor suppressor protein

“…Furthermore, in a signaling cascade conserved from yeast to mammals, mitochondrial sAC senses metabolically produced CO 2 via HCO 3 − to regulate oxidative phosphorylation [21, 22]. These studies establish sAC as a pH/metabolic sensor in mammalian cells [14, 16, 17, 21–24]. As a pH/metabolic sensor, sAC activity is poised to reflect both extracellular and intracellular changes normally encountered by cells during transformation and, therefore, sAC has the potential to influence tumorigenesis.…”

Amplification of FSH signalling by CFTR and nuclear soluble adenylyl cyclase in the ovary

“…Interestingly, sAC is abundantly expressed in a wide variety of epithelial cells throughout the body, including the airway, kidney and choroid plexus . One of the roles of sAC in these epithelial cells is to sense the HCO 3 − /CO 2 concentration and regulate ion channels and transporters, including CFTR, and transporters whose activity is modulated by cAMP . Thus, it has been proposed that sAC may play an important role in the regulation of electrolyte and pH homeostasis .…”

“…One of the roles of sAC in these epithelial cells is to sense the HCO 3 − /CO 2 concentration and regulate ion channels and transporters, including CFTR, and transporters whose activity is modulated by cAMP . Thus, it has been proposed that sAC may play an important role in the regulation of electrolyte and pH homeostasis . In addition, sAC is also expressed in excitable cells, such as neurons and insulin‐secreting beta cells, immune cells, as well as osteoclast and osteoblast .…”