Proton sensing G protein coupled receptors and TRPC channels - novel players in neuronal proliferation and development

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In order for our human body to function properly, it has to offer a stable environment to its building blocks, the cells. Cells work best in a tightly controlled environment in which factors such as nutrient supply and pH are kept more or less constant. Any change in environmental settings may have detrimental effects on cell functioning and can even cause cell death. One of the parameters that is kept constant is the extracellular proton concentration that determines the tissue pH. A too low (acidic) extracellular pH (equivalent to a high extracellular proton concentration) has been shown to cause cell death. One such example for acidosis-induced cell death is cell loss following a stroke (ischemia). Surprisingly, however, under certain conditions a low external pH promotes rather than compromises cell survival. This astonishing observation has been made in cancerous tissue: here, extracellular acidosis is not only tolerated by cancer cells, but it is essential for cancer progression and formation of metastases. An equally intriguing finding is that the detrimental effects of ischemia (in large part due to acidosis of the ischemic tissue) is less dramatic and more readily reversible in younger compared with old patients. All this suggests that the ability of cells to respond to a low extracellular pH with enhanced survival rather than death may be cell-type specific and can to some extent depend on the developmental stage of the tissue involved. Cancers mimic early developmental stages of tissues in that both cancer cells and developing cells continually multiply to build up tissue mass. We have recently made the important observation that developing brain cells, just like cancer cells, respond to external acidification with increased cell survival rather than cell death. This surprise finding has led us to propose the following project: to investigate how a fall in extracellular pH promotes survival of normal, developing brain cells. This study is the first to address the effects of extracellular acidosis on developing tissue and will open up an entirely new field of research. Understanding the cellular mechanism triggered by a fall in external pH that induce cell survival in normal cells will provide important insights into how cancerous cells may take advantage of these pathways and use them to enhance survival of transformed as opposed to unftransformed cells. Ultimately, it may provide us with novel therapeutic strategies to combat debilitating diseases such as cancer, which affect 1 in 3 people.