Elevated carbon dioxide blunts mammalian cAMP signaling dependent on inositol 1,4,5-triphosphate receptor-mediated Ca2+ release.
Elevated carbon dioxide blunts mammalian cAMP signaling dependent on inositol 1,4,5-triphosphate receptor-mediated Ca2+ release.
复制标题
二氧化碳升高的哺乳动物cAMP信号转导取决于肌醇1,4,5-三磷酸受体介导的Ca2+释放。
DOI：
10.1074/jbc.m112.349191
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发表时间：
2012-07-27
期刊：
影响因子：
--
通讯作者：
Cann MJ
中科院分区：
文献类型：
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作者：
Cook ZC;Gray MA;Cann MJ
背景：二氧化碳浓度升高对哺乳动物细胞有毒性作用。结果：分子CO2可降低细胞内cAMP依赖的细胞内钙离子浓度。结论：CO2可通过IP3介导的钙离子释放改变细胞的生理过程。意义：二氧化碳介导的钙信号的改变可能加强了二氧化碳对细胞的有害影响。二氧化碳浓度升高通常对动物细胞有害，这表明与细胞生物学中的核心过程相互作用。我们证明，二氧化碳浓度升高会钝化G蛋白激活的cAMP信号。CO2的作用与细胞内外pH的变化无关，与激活cAMP信号通路的机制无关，也与细胞环境无关。药理学和遗传学工具的结合表明，二氧化碳升高对cAMP水平的影响需要IP3受体的活性。与这些发现一致的是，二氧化碳引起稳态胞浆钙浓度的增加，在没有IP3受体的情况下或在非特异性酸化条件下观察不到。我们研究了cAMP依赖的抑制异构体3 Na+/H+逆向转运体(NHE3)，以证明与二氧化碳介导的细胞内cAMP减少的功能相关。与细胞生物化学一致，高二氧化碳通过IP3受体依赖的机制消除了cAMP对NHE3功能的抑制作用。
Background: Elevated CO2 is toxic to mammalian cells. Results: Molecular CO2 reduces cellular cAMP dependent on intracellular Ca2+. Conclusion: CO2 can alter cellular physiological processes through IP3-mediated Ca2+ release. Significance: Altered Ca2+ signaling mediated by CO2 might underpin the detrimental effects of CO2 on the cell. 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.