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Synaptic receptors for low pH in
extracellular space: metabotropic
receptors are an underestimated factor
in stroke
Sergei V. Fedorovich, Tatsiana G. Dubouskaya, Tatsiana V. Waseem
2020, 15 (11):
2033-2034.
doi: 10.4103/1673-5374.282249
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).
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