Protons as Messengers of Intercellular Communication in the Nervous System

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.

Novel hybrid action of GABA mediates inhibitory feedback in the mammalian retina

“…Modest changes in synaptic cleft pH modulate the voltage dependence of photoreceptor Ca V channel activation and powerfully alter glutamate release from photoreceptors [27], bolstering the evidence that activity-driven changes in pH in the synaptic cleft are responsible for synaptic regulation. While slow extracellular acidification normally accompanies neuronal depolarization due to the metabolic activity required to maintain ionic gradients [32], membrane mechanisms capable of rapid pH change, e.g., Na + /H + exchangers (NHEs), Na + /HCO 3 − cotransporters (NBCs), anion exchangers (AEs), Na + /Cl − /HCO 3 − exchangers (NCBEs), and Na + -driven Cl − /HCO 3 − exchangers (NDCBEs), vesicular ATPases (V-ATPases), monocarboxylic acid transporters (MCTs), and intra- and extracellular carbonic anhydrase enzymes (CAs) [33], are known to be or are likely present throughout the retina. Yet it remains unclear what exact adaptations have allowed for acidification to constitute this feedback mechanism.…”

Histidine Residues Are Responsible for Bidirectional Effects of Zinc on Acid-Sensing Ion Channel 1a/3 Heteromeric Channels

“…To date, four genes ( ASIC1 – ASIC4 ), encoding at least six ASIC subunits, have been cloned [ 2 ]. Each ASIC subunit has two transmembrane domains, a large ectodomain with rich histidine residues, and short cytoplasmic N- and C-termini [ 15 , 16 , 17 ]. The acid-sensing ion channel 1a (ASIC1a) has distinct properties as compared with ASIC3 [ 15 ].…”

Horizontal Cell Feedback to Cone Photoreceptors in Mammalian Retina: Novel Insights From the GABA-pH Hybrid Model

“…This clear and simple relationship demonstrates how activity-driven changes in pH in the synaptic cleft can affect synaptic regulation ( Figure 3 ). Whether adaptations to the expression of Na + /H + exchangers (NHEs), HCO 3 − transporters (NBCs, AEs, NCBEs, and NDCBEs), V-ATPases, monocarboxylic acid transporters (MCTs) and carbonic anhydrase (CA; Soto et al, 2018 ), have occurred in the outer retina to mitigate or potentiate the contribution of acidification to this feedback mechanism is not known.…”