Elevated carbon dioxide blunts mammalian cAMP signaling dependent on inositol 1,4,5-triphosphate receptor-mediated Ca2+ release.
Elevated CO(2) is generally detrimental to animal cells, suggesting an interaction with core processes in cell biology. We demonstrate that elevated CO(2) blunts G protein-activated cAMP signaling. The effect of CO(2) is independent of changes in intracellular and extracellular pH, independent of the mechanism used to activate the cAMP signaling pathway, and is independent of cell context. A combination of pharmacological and genetic tools demonstrated that the effect of elevated CO(2) on cAMP levels required the activity of the IP(3) receptor. Consistent with these findings, CO(2) caused an increase in steady state cytoplasmic Ca(2+) concentrations not observed in the absence of the IP(3) receptor or under nonspecific acidotic conditions. We examined the well characterized cAMP-dependent inhibition of the isoform 3 Na(+)/H(+) antiporter (NHE3) to demonstrate a functional relevance for CO(2)-mediated reductions in cellular cAMP. Consistent with the cellular biochemistry, elevated CO(2) abrogated the inhibitory effect of cAMP on NHE3 function via an IP(3) receptor-dependent mechanism.
School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, United Kingdom.
Zara C
ZC
Cook
Michael A
MA
Gray
Martin J
MJ
Cann
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D002245:Carbon Dioxide / Q000502:physiology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D048293:Didelphis; D020536:Enzyme Activators / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000502:physiology; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism
D020536:Enzyme Activators; D053496:Inositol 1,4,5-Trisphosphate Receptors; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D017923:Sodium-Hydrogen Exchangers; D002245:Carbon Dioxide; D005576:Colforsin; D000242:Cyclic AMP; D000262:Adenylyl Cyclases