Elevated Carbon Dioxide Blunts Mammalian cAMP Signaling Dependent on Inositol 1,4,5-Triphosphate Receptor-mediated Ca2+ Release

Cook, Z.C.; Gray, M.A.; Cann, M.J.

Abstract

Elevated CO2 is generally detrimental to animal cells, suggesting an interaction with core processes in cell biology. We demonstrate that elevated CO2 blunts G protein-activated cAMP signaling. The effect of CO2 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 CO2 on cAMP levels required the activity of the IP3 receptor. Consistent with these findings, CO2 caused an increase in steady state cytoplasmic Ca2+ concentrations not observed in the absence of the IP3 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 CO2-mediated reductions in cellular cAMP. Consistent with the cellular biochemistry, elevated CO2 abrogated the inhibitory effect of cAMP on NHE3 function via an IP3 receptor-dependent mechanism.

Citation

Cook, Z., Gray, M., & Cann, M. (2012). Elevated Carbon Dioxide Blunts Mammalian cAMP Signaling Dependent on Inositol 1,4,5-Triphosphate Receptor-mediated Ca2+ Release. Journal of Biological Chemistry, 287(31), 26291-26301. https://doi.org/10.1074/jbc.m112.349191

• Journal Article Type: Article
• Publication Date: Jul 27, 2012
• Deposit Date: Aug 13, 2012
• Publicly Available Date: Mar 2, 2015
• Journal: Journal of Biological Chemistry
• Print ISSN: 0021-9258
• Electronic ISSN: 1083-351X
• Publisher: American Society for Biochemistry and Molecular Biology
• Peer Reviewed: Peer Reviewed
• Volume: 287
• Issue: 31
• Pages: 26291-26301
• DOI: https://doi.org/10.1074/jbc.m112.349191
• Keywords: Adenylate cyclase (Adenylyl cyclase), Carbon dioxide, Cyclic AMP (cAMP), Inositol 1,4,5-trisphosphate, Parathyroid hormone.
• Public URL: https://durham-repository.worktribe.com/output/1497608