Abstract: In the brain, extracellular pH could decrease in certain diseases. Acidification, however, is especially attributable for stroke. Lactate accumulation in the absence of anaerobic respiration is the main, but not the only, reason for lowering pH in this condition (Wemmie et al., 2013). In addition, local pH changes in the synaptic cleft may result from the release of acidic content of synaptic vesicles (Sinning and Hubner, 2013). Acidification is able to damage or even kill a neuron. The damaging effect of low pH can be mediated by a direct effect of protons on enzymes or transport systems. It can also, however, be mediated by specific receptors (Wemmie et al., 2013; Levin and Buck, 2015). The most well studied class of pH receptors is ionotropic acid-sensing ion channels (ASIC). These are ion channels which are permeable for sodium and calcium. They open in response to extracellular acidification. Activation of these receptors could lead to neuronal death (Wemmie et al., 2013). ASIC-induced neuronal death is appeared to be involved in stroke-induced brain damage. This suggestion is supported by the fact that amiloride, which inhibits ASIC, has a neuroprotective effect in stroke (Xiong et al., 2004). Amiloride is able to reduce currents through ASIC types, however, the exact structural basis for this phenomenon is still not very clear (Wemmie et al., 2013). Generally, the majority of hormones and neurotransmitters exert their action via two main types of receptors. These are ionotropic and metabotropic receptors. The function of ionotropic channels is mediated by ion channel opening and ion fluxes through plasma membranes. The function of metabotropic receptors is mediated by G-proteins and enzymatic reactions. In this case, a cellular response will be slower and it will be rather fine tuning than the “all-ornothing” effect. This seems to be the key difference between ionotropic and metabotropic receptors. Based on the knowledge in this field, the existence of both metabotropic and ionotropic receptors, which could respond to changes in extracellular pH, is possible. By now, proteins with this function have been found on plasma membrane of eukaryotic cells (Levin and Buck, 2015). The role of metabotropic receptors for low pH in regulation of activity of central nervous system cells, however, is still not very understood. Recently, we have shown that the activation of metabotropic receptor for low pH on plasma membrane of isolated neuronal presynaptic endings, most likely ovarian cancer G-protein- coupled receptor 1 (OGR1), leads to mitochondria depolarization (Dubouskaya et al., 2018).