Abstract
In this review, evidence demonstrating that protons (H+) constitute a complex, regulated intercellular signaling mechanisms are presented. Given that pH is a strictly regulated variable in multicellular organisms, localized extracellular pH changes may constitute significant signals of cellular processes that occur in a cell or a group of cells. Several studies have demonstrated that the low pH of synaptic vesicles implies that neurotransmitter release is always accompanied by the co-release of H+ into the synaptic cleft, leading to transient extracellular pH shifts. Also, evidence has accumulated indicating that extracellular H+ concentration regulation is complex and implies a source of protons in a network of transporters, ion exchangers, and buffer capacity of the media that may finally establish the extracellular proton concentration. The activation of membrane transporters, increased production of CO2 and of metabolites, such as lactate, produce significant extracellular pH shifts in nano- and micro-domains in the central nervous system (CNS), constituting a reliable signal for intercellular communication. The acid sensing ion channels (ASIC) function as specific signal sensors of proton signaling mechanism, detecting subtle variations of extracellular H+ in a range varying from pH 5 to 8. The main question in relation to this signaling system is whether it is only synaptically restricted, or a volume modulator of neuron excitability. This signaling system may have evolved from a metabolic activity detection mechanism to a highly localized extracellular proton dependent communication mechanism. In this study, evidence showing the mechanisms of regulation of extracellular pH shifts and of the ASICs and its function in modulating the excitability in various systems is reviewed, including data and its role in synaptic neurotransmission, volume transmission and even segregated neurotransmission, leading to a reliable extracellular signaling mechanism.
Highlights
We first review evidence related to extracellular proton production and of its regulation and control mechanisms, the structure and functions of the Acid Sensing Ion Channels (ASIC) are discussed, along with other extracellular H+ concentration gradient (pH) sensing molecules, and evidence of the role of proton signaling mechanism in specific synaptic transmission, volume neurotransmission, and segregated specific proton production are reviewed.Extracellular pH is a highly controlled variable, with many regulatory processes maintaining it within a restricted value, which in vertebrates is close to neutrality
To define the extent at which proton concentration in synaptic like nano-domains may activate the ASICs, a construct in HEK293T cells was devised, showing that H+ current passing through light activated Archaerodopsin3 or voltage-gated proton channel (Hv1) can activate closely coupled ASIC channels and induce its activation in closely located “sniffer” cells (Zeng et al, 2015). Modeling of this system showed that proton currents may lead to a pH change of almost 4 units and of 0.6 within 10–100 nm (Zeng et al, 2015). These results demonstrate that extracellular H+ concentration changes in nano-domains can activate the ASICs
Extracellular pH changes modulate diverse cellular processes such as neuronal excitability, neurotransmitter release and postsynaptic responses, because pHe modulates the activity of different neuronal ion channels apart from the specific H+ sensing channels, including voltage-dependent Ca2+, K+, and Na+ channels, glutamate and GABA receptors (GABAR), and Transient Receptor Potential-1 (TRPV1), among others (Chesler, 2003; Chiacchiaretta et al, 2017)
Summary
We first review evidence related to extracellular proton production and of its regulation and control mechanisms, the structure and functions of the Acid Sensing Ion Channels (ASIC) are discussed, along with other extracellular pH sensing molecules, and evidence of the role of proton signaling mechanism in specific synaptic transmission, volume neurotransmission, and segregated specific proton production are reviewed.Extracellular pH is a highly controlled variable, with many regulatory processes maintaining it within a restricted value, which in vertebrates is close to neutrality. A mass of neurons leads to an increase in extracellular H+ concentration, which activates ASICs, expressed either at the synaptic or extrasynaptic level.
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