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

为了让我们的身体正常运作，它必须为它的组成部分--细胞--提供一个稳定的环境。细胞在严格控制的环境中工作得最好，在这种环境中，营养供应和pH等因素或多或少保持不变。环境设置的任何变化都可能对细胞功能产生不利影响，甚至可能导致细胞死亡。保持不变的参数之一是细胞外质子浓度，它决定了组织的pH值。细胞外pH过低(酸性)(相当于较高的胞外质子浓度)会导致细胞死亡。酸中毒引起的细胞死亡的一个这样的例子是中风(缺血)后的细胞丢失。然而，令人惊讶的是，在某些条件下，较低的外部pH促进而不是损害细胞存活。这一令人惊讶的观察已经在癌症组织中进行：在这里，细胞外酸中毒不仅是癌细胞所耐受的，而且是癌症进展和转移形成所必需的。另一个同样耐人寻味的发现是，与老年患者相比，年轻患者的缺血有害影响(很大程度上是由于缺血组织的酸化)不那么明显，更容易逆转。所有这些都表明，细胞对低细胞外pH的反应能力提高了生存能力，而不是死亡，这可能是细胞类型特有的，在一定程度上可能取决于所涉及组织的发育阶段。癌症类似于组织的早期发育阶段，因为癌细胞和发育中的细胞都在不断繁殖，以形成组织块。我们最近做了一个重要的观察，发育中的脑细胞就像癌细胞一样，对外部酸化做出反应，细胞存活率增加，而不是细胞死亡。这一令人惊讶的发现导致我们提出了以下项目：研究细胞外pH的下降如何促进正常发育中的脑细胞的存活。这项研究是第一次解决细胞外酸中毒对发育中组织的影响，并将开辟一个全新的研究领域。了解外界pH下降引发的诱导正常细胞存活的细胞机制将为肿瘤细胞如何利用这些途径并利用它们来提高转化细胞的生存能力提供重要的见解。最终，它可能为我们提供新的治疗策略，以对抗癌症等令人衰弱的疾病，这些疾病影响着三分之一的人。

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.