Stimulation of mammalian G-protein-responsive adenylyl cyclases by carbon dioxide.
Carbon dioxide is fundamental to the physiology of all organisms. There is considerable interest in the precise molecular mechanisms that organisms use to directly sense CO(2). Here we demonstrate that a mammalian recombinant G-protein-activated adenylyl cyclase and the related Rv1625c adenylyl cyclase of Mycobacterium tuberculosis are specifically stimulated by CO(2). Stimulation occurred at physiological concentrations of CO(2) through increased k(cat). CO(2) increased the affinity of enzyme for metal co-factor, but contact with metal was not necessary as CO(2) interacted directly with apoenzyme. CO(2) stimulated the activity of both G-protein-regulated adenylyl cyclases and Rv1625c in vivo. Activation of G-protein regulated adenylyl cyclases by CO(2) gave a corresponding increase in cAMP-response element-binding protein (CREB) phosphorylation. Comparison of the responses of the G-protein regulated adenylyl cyclases and the molecularly, and biochemically distinct mammalian soluble adenylyl cyclase revealed that whereas G-protein-regulated enzymes are responsive to CO(2), the soluble adenylyl cyclase is responsive to both CO(2) and bicarbonate ion. We have, thus, identified a signaling enzyme by which eukaryotes can directly detect and respond to fluctuating CO(2).
Townsend
Philip D
PD
School of Biological and Biomedical Sciences, Durham University, Durham, UK.
Holliday
Phillip M
PM
Fenyk
Stepan
S
Hess
Kenneth C
KC
Gray
Michael A
MA
Hodgson
David R W
DR
Cann
Martin J
MJ
D000262:Adenylyl Cyclases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002245:Carbon Dioxide / Q000494:pharmacology*; D002460:Cell Line; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008969:Molecular Sequence Data; D051381:Rats; D016415:Sequence Alignment
D007527:Isoenzymes; D002245:Carbon Dioxide; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases