Trends in Endocrinology & Metabolism
ReviewCO2/HCO3−-responsive soluble adenylyl cyclase as a putative metabolic sensor
Section snippets
sAC as a metabolic pH sensor
Most catabolic processes converge on the citric acid cycle and on the electron transport chain, the end products of which are CO2 and ATP. In solutions with increasing partial pressures of CO2, water and CO2 are converted to HCO3− and H+, and vice versa (Fig. 4a). Unaided, this reaction reaches equilibrium in minutes, but in the presence of the ubiquitously expressed carbonic anhydrases (CA), it occurs almost instantaneously 24. CAs are represented in mammals by a large family whose members
Cyanobacteria
sAC is closely related to cyanobacterial adenylyl cyclases (ACs) 2, and HCO3− regulation is conserved across this vast evolutionary distance 9. Cyanobacteria are thought to be responsible for the photosynthesis that transformed the early pre-Cambrian atmosphere from one rich in CO2 to one rich in O2 (Ref. 35). In cyanobacteria, cAMP levels change in response to environmental conditions such as nutritional availability, and because they are photosynthetic, nutrients consist of CO2 and light (
Summary
sAC defines a novel cAMP signaling pathway with the potential to respond to pH, intracellular metabolism and ionic flux. As CO2/HCO3− is the main buffering system in the cell, levels of HCO3− would present an excellent signal for cellular homeostasis, and a direct link between CO2/ HCO3− levels and metabolism has been suggested 17, 18, 19, 20. In metabolism, pHi and/or cAMP effector proteins regulate key enzymes by direct modification or alterations in gene transcription. Therefore,
Acknowledgements
We would like to thank Geoffrey Pitt and Walter Boron, and also the members of the Levin/Buck laboratory for comments on the manuscript. Work in the authors’ laboratory is supported by NIH grants HD38722 (LRL), GM62328 (JB) and HD42060 (JB), and by the Irma T. Hirschl Trust (JB).
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