Prerpints.org logo
Preprint
Review

This version is not peer-reviewed.

Proton Mechanisms of Neurotransmission and Calcium Signalling for Impulse Initiation, Development and Propagation

A peer-reviewed article of this preprint also exists.

Submitted:

25 May 2023

Posted:

26 May 2023

Read the latest preprint version here

Abstract
Protons are gaining increasing attention as neurotransmitters due to their extraordinary abilities to rapidly transfer electrical charge, mobilize cellular calcium and modulate ion channels. How all this is possible is currently the subject of in-depth studies and discussions concerning not only neurophysiology, but also biological materials for artificial intelligence. In this short review, some biochemical mechanisms are described by which protons, in combination with calcium, can initiate firing in sensory neurons and transmit impulse across synapses. Furthermore, mechanisms are put forward concerning how three neurotransmitters, glutamate, gamma-aminobutyric acid and acetylcholine, are able to generate protons. The results of the numerous experimental works taken into consideration indicate that protons can play a fundamental role both in the generation and in the transmission of the nerve impulse.
Keywords: 
lipid membrane
;  
excitable cells
;  
vesicles
;  
H+ ion
;  
Ca2+ signaling
;  
calcium
;  
binding proteins
;  
signal transduction
;  
G-protein coupled receptors
Subject: 
Biology and Life Sciences  -   Neuroscience and Neurology

Introduction

The dual purpose of this review is: 1) to describe some biochemical pathways for the transmission of the nerve impulse activated by H+ and Ca2+ ions; 2) identify three endogenous sources of H+ ions, neglected until now.
The fundamental role of Na+ e K+ ions in nerve transmission was demonstrated by eighteen years of experimental work by Hodgkin and Huxley.1 H+ and Ca2+ ions were studied less, although Hodgkin and Huxley noted the significant role of Ca2+ as far back as 1949 (Hodgkin1976, Fig.7).2 Subsequent studies confirmed the fundamental role of Ca2+ in proper transmission3–5 and showed that dysfunctions in the homeostasis of Ca2+ can cause neurodegenerative diseases. The interest in H+ ions, identified below with the current terminology as “protons”, picked up with technical progress in instruments after 1980.6–8 Nerve impulses can last no more than 10 ms, pH transients and calcium spikes less than 2 ms, hence require sophisticated instruments for their study.
It is known that both Ca2+ ions and protons are ubiquitous in organisms, at concentrations that are strictly correlated.9–11 A widespread lasting increase in their concentration produces the pathological condition known as acidosis, whilst a local and temporary increase is used currently by cells as a signal, in physiological conditions.12,13 The correlation between protons and Ca2+ ions is fundamental for the transmission of the signal and depends on the high degree of solubility in an acid environment of protein-calcium complexes and calcium compounds, such as carbonates and phosphates, known to be calcium-buffering molecules. In cells in a static state most cytosolic calcium is immobilized in these compounds. When the stimulus reaches the cell membrane activating a strongly acidifying enzyme, such as an esterase, the enzymatic action produces protons and hence locally and temporarily lowers pH. The acidity dissolves the calcium compounds, which can therefore pass into solution as Ca2+, producing calcium spikes, of intensity and duration proportional with the quantity of protons freed.9,14,15 It has been calculated that in mitochondria a fall of one unit of pH produces a 100-fold increase in the concentration of Ca2+.16 Clearly, the acidifying action of esterases is an important characteristic enabling the transformation of the chemical signal into transient electric charges and the basis for the release of Ca2+ from cellular stores and the influx of extracellular Ca2+. However, surprisingly, this characteristic has almost entirely been ignored in scientific publications.11 Table 1 sets out some examples of esterases and the acids they produce, which can solubilize cytosolic calcium.
With an atomic mass about 23 times lower than sodium and a radius of about 0.08 nm, the proton is the smallest and most mobile ion in existence. Its high level of permeability through the phospholipidic membrane is about 7-times that of Na+.24 The elemental charge of the proton is the same as for other individual monovalent cations, at 1.602 x 10-19 C. However, protons can transport the charge much more quickly,25,26 via proton-hopping.27,28 In addition to reacting with water, they can interact with amino acids and proteins and modulate29 a large variety of channels and receptors, such as Voltage Gated Calcium Channels (VGCC/CaV),30,31 Store Operated Calcium channels (SOC),32 calcium-activated potassium channels (KCa),33,34 inward rectifier potassium channels (Kir),35,36 voltage gated proton channels (Hv),37 proton gated Acid Sensing Ion Channels (ASIC),38–40 multimodal Transient Receptor Potential channels (TRP),41,42 and G-protein Coupled Receptors (GPCR).43 The interaction depends on the species, the extracellular or intracellular position of the protons, their concentration and the type of channel.44 Many channels, including ASIC and TRPV1, mainly trigger activation, others such as VGCC45 and TRPV546 have a control or inhibitory function.
To sum up, protons are tiny ionic particles that in an aqueous environment are acidic and highly mobile, able to rapidly transfer positive charges and to temporarily modify pH, Ca2+ concentration, electrical potential and the protein structure, as a result activating numerous receptors. Due to these extraordinary chemical and physical properties they are used in the preparation of organic electro-conductive materials47,48 and are attracting increasing attention as neurotransmitters.12,13,49–58 They have been shown to have an essential role at the synaptic level58–62 and it has been posited that they are responsible for conduction in myelinated axons.57,63 Some authors have also posited a significant role in the transmission and modulation of the signal in the nervous system generally.13,38,64 However, the endogenous sources of the protons have yet to be determined. There are four candidates: Na-H exchangers, V-ATPases, carbonic anhydrases and AE3 chloride-bicarbonate exchanger,12,13,65,66 which however appear to be insufficient.66 Specifically, Soto et al.13 rightly observe: “A problem of classifying protons as neurotransmitters is related to the fact that its regulated release is always a co-release with classical neurotransmitters”. In addition, some criticisms have been levelled against the theory of Hodgkin and Huxley; for example, it does not explain the origin of the firing of neurons.67 X-ray crystallography and cryo-electron microscopy have revealed the structure of many ionic channels in the inactivated/open state and in some cases the amino acid residues involved in gating.68 However, a knowledge of the structures of the intermediate states at the atomic level is required in order to better understand the origin of the movement of charges in the gating mechanism.69 These problems could be overcome more simply if neurotransmitters and second messengers were included among the possible sources of protons, given that these molecules can generate protons, i.e., new mobile charges as described in paragraph 2 of the discussion and protons can trigger firing and open channels, as described in paragraph 1.

Methods

A review and critical assessment was made of the scientific publications dealing with the topic between 01.01.1950 and 25.05.2023, all available online.

Results and Discussion

1. Pre-synaptic transmission of the impulse in sensory neurons

Protons can contribute to the generation and transmission of impulses in sensory neurons via biochemical mechanisms that differ in modality and effects.70
For the perception of tastes there are substantial differences between vertebrates and insects.71
In the specific case of neurons sensitive to a sour taste, it has been shown in mammals that protons can directly cause firing by opening OTOP1,72 TRP73,74 and perhaps ASIC75 type channels. OTOP1 channels induce a change in the potential of the membrane, directly importing protons into the cytosol.73,76 The resulting fall in cytosolic pH solubilizes calcium-buffering molecules and reduces the action of Kir channels36 and this may cause further depolarization.76 Any activation of ASIC and TRPV1 channels can produce proton-induced calcium influx.44 The increase in Ca2+ concentration in the cytosol modulates calcium-activated potassium channels.77,78
The pathway is more complex in the case of sensory neurons with GPCR-type metabotropic receptors at the distal termination of the axon; these are very common in mammals79,80 for the transmission of visual stimuli,81 smell,82,83 nociceptive stimuli84 and taste, limited to taste/flavour perceptions of sweet, bitter, umami and kukumi.85–87 In these cases, the biochemical mechanism begins with the activation of a phospholipase C (PLC).88,89 The PLC hydrolyzes the phosphatidylinositol (4,5)-bisphosphate of the neuron membrane, this reaction for several enzyme isoforms is pH and Ca2+ dependent.90–92 It is important to note that the reaction can be acidifying and autocatalytic, because inside the neuron hydrolysis produces inositol 1,4,5-trisphosphate (IP3) and protons,18,55 which in turn free Ca2+,93,94 solubilizing the calcium-buffering molecules hence fostering a gradual increase in enzymatic activity. The acidifying action has been confirmed experimentally at the presynaptic termination.95–97 The protons and IP3 released from the PLC by the enzymatic action of hydrolysis produce a threefold increase in cytosolic Ca2+ concentration due to: 1) the lowering of pH and resulting solubilization of the calcium-buffering molecules, 2) Ca2+ release from endoplasmic reticulum stores, 3) Ca2+ influx by stimulation of the SOCs. Since the activation of the SOCs induces the depolarization of the neuron membrane,98 the influx of Ca2+ can be seen as the first step in depolarization. A second step may follow rapidly with the closing of Kir-type channels and the opening of low threshold VGCC/CaV channels99–102 permeable to Ca2+, TRP12,42,55,103 and ASICs104 channels permeable to Ca2+ e Na+.105 The opening of the channels enables the influx of further Ca2+ and Na+. The above studies jointly demonstrate that protons, together with Ca2+ ions, can start the process of depolarizing the membrane not only in neurons sensitive to a sour taste, but also in many other neurons with GPCR-type receptors.
It is likely that the three ions, H+, Ca2+ and Na+ contribute in differing degrees to depolarization until the threshold value is reached. When the threshold value is exceeded Voltage Gated Sodium Channels (NaV) open, generating the action potential.1,106 This produces the exocytosis of the vesicles and release of the neurotransmitters into the synaptic cleft.107,108 In the following repolarization phase the NaV channels close and the Kv,1,109,110 KCa, Kir and Hv proton channels37,111 open enabling the efflux respectively of the K+ ions and the protons leading to the immobilization of Ca2+ and the return to static conditions. Pumps and exchangers are secondary contributors to the entire process.
In the eye, the activation of GPCRs via the PLC/IP3 pathway occurs by means of the cells containing melanopsin, such as the ganglion cells of the iris, whilst the cells of the retina containing rhodopsin and the cells of the auricular cochlea follow a different pathway, via PDE/cGMP.112,113 In this case, the protons are generated by the hydrolysis of cGMP and the dissociation of acid glutamate, as described below in paragraph 2.
In relation to the sensory neurons that transmit mechanical stimuli, it is believed that in mammals these neurons generally respond via mechanoelectrical channels.114 The physical stimulus induces the opening of ionic channels enabling the influx of Ca2+, depolarization and the generation of the action potential. The mechanisms for the activation of the channels are not clear.115 In some cases, ASIC channels116 or GPCR receptors117 are involved. It has been shown that the G protein-coupled receptor OGR1 (GPR68) responds to mechanical stimuli and to protons via the PLC/IP3 pathway.118,119
To sum up, for the above sensorial neurons, with ionotropic channels of the OTOP, TRP, ASIC type or metabotropic channels of the GPCR type, protons are essentials for increased cytosolic Ca2+ concentration. With limitation to these cases is it therefore possible to respond to the criticisms of the Hodgkin and Huxley theory and to affirm that protons, inducing with Ca2+ the first depolarization step, via proton-influx and/or proton-induced calcium influx, may be at the origin of firing.

2. Synaptic Transmission of the Impulse

In two prior publications we have described how protons may be generated in different cells by second messengers with the chemical structure of an ester or anhydride, such as ATP, IP3, S1P, NAADP, cADPR, cAMP or cGMP, by the hydrolytic action of specific enzymes.11,18
The hydrolysis of an ester or anhydride always produces an acid, in these cases phosphoric acid or a derivation, which can rapidly dissociate, freeing protons. Table 1 in the introduction provides some examples of the hydrolysis of esters in organisms. Schematic representations of the reaction are available in many cases, for example for: ATP (Feng, equation 5),120 IP3 (Huang, Supplementary information, Fig.S1),55 cAMP (Barbosa, Fig.3)121 and cGMP (Rybalkin Fig.1).122 However, it is not easy to find the complete representation, because most texts inexplicably fail to mention protons.
Neurotransmitters include compounds with an acid or ester type structure that can therefore generate protons. Below, three fundamental neurotransmitters are considered, released in the ribbon-type synapses by vesicle exocytosis: acetylcholine (ACh), gamma-aminobutyric acid (GABA) and glutamate (Glu). ACh is an ester, GABA and Glu are acid molecules. It is worth clarifying something regarding the latter: glutamate is the name given to a neutral salt and this can lead to confusion. In fact, for the acid strength GABA and Glu are very similar amino acids: they have respectively 4.0 and 4.3 pKa. Therefore, in vesicles where the pH is acidic,123–127 they are both partially undissociated, in the protonate form; therefore, for the sake of coherence, like GABA, Glu should be called acid glutamate. When they are released in a neutral or slightly alkaline environment, such as the synaptic cleft in the static state, these undissociated acid molecules tend to dissociate, each in its respective anion and a proton, as shown in Table 2.
Therefore, it is evident that vesicle exocytosis produces inter-synaptic acidification13,58,126,128–131 through the release of protons by the two acid neurotransmitters, Glu or GABA and that the two neurotransmitters are, in this case, the principal source of the protons. The importance of this source is shown by the fact that the organism consumes energy to recycle Glu and GABA in the vesicles and to protonate them once again sufficiently rapidly to reuse them.132–135
Regarding the ACh, which has the molecular structure of an ester, the protons are released by the acetic acid produced by the hydrolytic split of the ester by the cholinesterases: acetylcholinesterase and butyryl-cholinesterase. The reaction is very rapid and produces choline and acetic acid. For a long time, it was believed that the acetic acid and choline, constituting the ACh, were neurologically inactive molecules. It is still believed that the activity of ACh concerns the entire molecule because the limited use of anticholinesterases inhibits the response in direct proportion to the inhibitor dose and the response increases with the accumulation of ACh.136 From this standpoint, cholinesterases have the sole function of rapidly eliminating the ACh, after its action. Today, we know that both constituents, choline and acetic acid, carry out a specific neurologically significant action74,137 and that acetylcholinesterase may be indispensable for the action of ACh.23,60 In addition, it has been posited that cholinergic transmission is due to the protonation of the postsynaptic membrane, caused by the acetic acid derived from the hydrolysis of ACh.23
If the hypothesis that ACh can also act via its constituents were confirmed, it would be easier to clarify a number of questions that have been perplexing for some time. In addition, the fact that the three neurotransmitters ACh, Glu and GABA can release protons explains the observation of Soto et al. regarding co-release, as cited in the introduction.
The protons released by Glu, GABA or ACh acidify the inter-synaptic space and can activate acid-sensitive receptors at the postsynaptic termination together with specific receptors for Glu, GABA and ACh. There are numerous proton-sensitive receptors in the postsynaptic termination,138 both ionotropic such as ASICs,39,116 TRPV1,41,139–141 CaV3142 and metabotropic, of the TASK type143 and GPCRs.43 The proton activation of the postsynaptic receptor can foster the opening of ionic channels,103,144 depolarization and the generation of a new action potential, enabling the impulse to continue.23,59,145
Furthermore, many ligand receptors, specific for Glu, GABA and ACh, of the GPCR type, such as Group1 Glu (Sun2016, Suh2018), GABAb,146 nicotinic α729,147 and muscarinic M1, M3 and M5148,149 receptors are activated by protons generated by PLCs. Ionotropic GABAa are also activated by the PLCs.150 On the contrary, most ionotropic postsynaptic receptors of glutamate are inhibited by the protons, particularly AMPARs,151 Kainate receptors152 and NMDARs.153,154
To sum up, the protons may act at the synaptic level in various ways and via a large number of receptors. However, since protons are highly mobile and reactive but have low specificity, it is logical to attribute to protons mainly the quantitative aspects of the mechanisms of neurotransmission, whilst the qualitative aspects could be modulated by variations in the frequency, intensity and duration of the proton impulse, by a parallel series of events such as variations in the concentration of Ca2+ and other ions such as Zn2+ and Mg2+, the type of other neurotransmitters involved, the receptors activated, their interrelations and their responses. In line with the general principle of co-release and co-transmission.155,156

Conclusions

The introduction points out the interdependence of protons and Ca2+ ions due to their chemical properties and it is useful to bear this in mind when seeking to understand the role of these ions in neurotransmission. The following paragraphs cite numerous experimental works the result of which, when taken together, provide an answer to the dual aim of this paper and support the hypothesis that protons may play a fundamental role both in the generation and the biochemical transmission of the nerve impulse. Specifically, paragraph 1 of the discussion describes how protons are able to trigger the depolarization of sensorial neurons by directly opening ionotropic channels and to activate GPCR receptors, via PLC/IP3 and the mobilization of Ca2+, thereby contributing to the generation of the action potential and the exocytosis of the vesicles. Paragraph 2 describes the mechanisms by which neurotransmitters in the vesicles, such as Glu, GABA and ACh, are able to become the sources of protons, generating them and, via the protons, fostering the transmission of the impulse through the synaptic cleft to the postsynaptic termination and beyond. To conclude, the role of protons in neurotransmission may be more important that has so far been believed and may in the future lead to many surprising discoveries.

Acknowledgements

I would like to express my lasting gratitude to Henrique Soto, Instituto de Fisiologia, BUAP, Puebla, for reading the manuscript and for his helpful and valuable suggestions.

References

  1. Hodgkin A, Huxley, AF A. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952;117(4):500-544. [CrossRef]
  2. Hodgkin AL. Chance and design in electrophysiology: an informal account of certain experiments on nerve carried out between 1934 and 1952. J Physiol. 1976;263(1):1-21. [CrossRef]
  3. Augustine GJ, Santamaria F, Tanaka K. Local Calcium Signaling in Neurons. Neuron. 2003;40(2):331-346. [CrossRef]
  4. Neher E, Sakaba T. Multiple Roles of Calcium Ions in the Regulation of Neurotransmitter Release. Neuron. 2008;59(6):861-872. [CrossRef]
  5. Bagur R, Hajnóczky G. Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling. Mol Cell. 2017;66(6):780-788. [CrossRef]
  6. Gruol D, Barker J, Huang L, McDonald J, Smith TJr. Hydrogen ions have multiple effects on the excitability of cultured mammalian neurons. Brain Res. 1980;183(1):247-252. [CrossRef]
  7. Krishtal O, Pidoplichko V. A receptor for protons in the nerve cell membrane. Neuroscience. 1980;5(12):2325-2327. [CrossRef]
  8. Bevan, S, Yeats, J. Protons activate a cation conductance in a sub-population of rat dorsal root ganglion neurones. J Physiol. 1991;433:145-161. [CrossRef]
  9. Swietach P, Youm JB, Saegusa N, Leem CH, Spitzer KW, Vaughan-Jones RD. Coupled Ca 2+ /H + transport by cytoplasmic buffers regulates local Ca 2+ and H + ion signaling. Proc Natl Acad Sci. 2013;110(22). [CrossRef]
  10. Deplazes E, White J, Murphy C, Cranfield CG, Garcia A. Competing for the same space: protons and alkali ions at the interface of phospholipid bilayers. Biophys Rev. 2019;11(3):483-490. [CrossRef]
  11. Molinari G, Nervo E. Role of protons in calcium signaling. Biochem J. 2021;478(4):895-910. [CrossRef]
  12. Zeng WZ, Xu TL. Proton production, regulation and pathophysiological roles in the mammalian brain. Neurosci Bull. 2012;28(1):1-13. [CrossRef]
  13. Soto E, Ortega-Ramírez A, Vega R. Protons as Messengers of Intercellular Communication in the Nervous System. Front Cell Neurosci. 2018;12:342. [CrossRef]
  14. OuYang, JB, Mellergård, P, Kristián, T, Kristiánova, V, Siesjö, BK. Influence of acid-base changes on the intracellular calcium concentration of neurons in primary culture. Exp Brain Res. 1994;101(2):265-271. [CrossRef]
  15. Garciarena CD, Malik A, Swietach P, Moreno AP, Vaughan-Jones RD. Distinct moieties underlie biphasic H + gating of connexin43 channels, producing a pH optimum for intercellular communication. FASEB J. 2018;32(4):1969-1981. [CrossRef]
  16. Nicholls DG, Chalmers S. The Integration of Mitochondrial Calcium Transport and Storage. J Bioenerg Biomembr. 2004;36(4):277-281. [CrossRef]
  17. Sun GY, Xu J, Jensen MD, Simonyi A. Phospholipase A2 in the central nervous system. J Lipid Res. 2004;45(2):205-213. [CrossRef]
  18. Molinari G. Is hydrogen ion (H+) the real second messenger in calcium signalling? Cell Signal. 2015;27(7):1392-1397. [CrossRef]
  19. Cazzolli R, Shemon A, Fang M, Hughes W. Phospholipid signalling through phospholipase D and phosphatidic acid. IUBMB Life Int Union Biochem Mol Biol Life. 2006;58(8):457-461. [CrossRef]
  20. Majerus PW, York JD. Phosphoinositide phosphatases and disease. J Lipid Res. 2009;50:S249-S254. [CrossRef]
  21. Schmid F, Fliegert R, Westphal T, Bauche A, Guse AH. Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Degradation by Alkaline Phosphatase. J Biol Chem. 2012;287(39):32525-32534. [CrossRef]
  22. Wollny T, Wątek M, Durnaś B, et al. Sphingosine-1-Phosphate Metabolism and Its Role in the Development of Inflammatory Bowel Disease. Int J Mol Sci. 2017;18(4):741. [CrossRef]
  23. Fillafer C, Koll YS, Schneider MF. Lipid Membrane State Change by Catalytic Protonation and the Implications for Synaptic Transmission. Membranes. 2021;12(1):5. [CrossRef]
  24. Bozdaganyan ME, Lokhmatikov AV, Voskoboynikova N, et al. Proton leakage across lipid bilayers: Oxygen atoms of phospholipid ester linkers align water molecules into transmembrane water wires. Biochim Biophys Acta BBA - Bioenerg. 2019;1860(6):439-451. [CrossRef]
  25. Volkov VI, Chernyak AV, Golubenko DV, et al. Hydration and Diffusion of H+, Li+, Na+, Cs+ Ions in Cation-Exchange Membranes Based on Polyethylene- and Sulfonated-Grafted Polystyrene Studied by NMR Technique and Ionic Conductivity Measurements. Membranes. 2020;10(10):272. [CrossRef]
  26. Brünig FN, Rammler M, Adams EM, Havenith M, Netz RR. Spectral signatures of excess-proton waiting and transfer-path dynamics in aqueous hydrochloric acid solutions. Nat Commun. 2022;13(1):4210. [CrossRef]
  27. Agmon N, Bakker HJ, Campen RK, et al. Protons and Hydroxide Ions in Aqueous Systems. Chem Rev. 2016;116(13):7642-7672. [CrossRef]
  28. Silverstein TP. The Proton in Biochemistry: Impacts on Bioenergetics, Biophysical Chemistry, and Bioorganic Chemistry. Front Mol Biosci. 2021;8:764099. [CrossRef]
  29. King JR, Ullah A, Bak E, Jafri MS, Kabbani N. Ionotropic and Metabotropic Mechanisms of Allosteric Modulation of α 7 Nicotinic Receptor Intracellular Calcium. Mol Pharmacol. 2018;93(6):601-611. [CrossRef]
  30. Simms B, Zamponi G. Neuronal voltage-gated calcium channels: structure, function, and dysfunction. Neuron. 2014;82(1):24-45. [CrossRef]
  31. Sharma A, Rahman G, Gorelik J, Bhargava A. Voltage-Gated T-Type Calcium Channel Modulation by Kinases and Phosphatases: The Old Ones, the New Ones, and the Missing Ones. Cells. 2023;12(3):461. [CrossRef]
  32. Kraft R. STIM and ORAI proteins in the nervous system. Channels. 2015;9(5):245-252. [CrossRef]
  33. Guéguinou M, Chantôme A, Fromont G, Bougnoux P, Vandier C, Potier-Cartereau M. KCa and Ca2+ channels: The complex thought. Biochim Biophys Acta BBA - Mol Cell Res. 2014;1843(10):2322-2333. [CrossRef]
  34. Sancho M, Kyle BD. The Large-Conductance, Calcium-Activated Potassium Channel: A Big Key Regulator of Cell Physiology. Front Physiol. 2021;12:750615. [CrossRef]
  35. Hibino H, Inanobe A, Furutani K, Murakami S, Findlay I, Kurachi Y. Inwardly Rectifying Potassium Channels: Their Structure, Function, and Physiological Roles. Physiol Rev. 2010;90(1):291-366. [CrossRef]
  36. Ye W, Chang RB, Bushman JD, et al. The K + channel K IR 2.1 functions in tandem with proton influx to mediate sour taste transduction. Proc Natl Acad Sci. 2016;113(2). [CrossRef]
  37. DeCoursey TE. Voltage and pH sensing by the voltage-gated proton channel, H V 1. J R Soc Interface. 2018;15(141):20180108. [CrossRef]
  38. Zeng WZ, Liu DS, Liu L, She L, Wu LJ, Xu TL. Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling. Sci Rep. 2015;5(1):14125. [CrossRef]
  39. Rook ML, Musgaard M, MacLean DM. Coupling structure with function in acid-sensing ion channels: challenges in pursuit of proton sensors. J Physiol. 2021;599(2):417-430. [CrossRef]
  40. Storozhuk M, Cherninskyi A, Maximyuk O, Isaev D, Krishtal O. Acid-Sensing Ion Channels: Focus on Physiological and Some Pathological Roles in the Brain. Curr Neuropharmacol. 2021;19(9):1570-1589. [CrossRef]
  41. Kweon HJ, Yu SY, Kim DI, Suh BC. Differential Regulation of Proton-Sensitive Ion Channels by Phospholipids: A Comparative Study between ASICs and TRPV1. Xu SZ, ed. PLOS ONE. 2015;10(3):e0122014. [CrossRef]
  42. Cao E. Structural mechanisms of transient receptor potential ion channels. J Gen Physiol. 2020;152(3):e201811998. [CrossRef]
  43. Sisignano M, Fischer MJM, Geisslinger G. Proton-Sensing GPCRs in Health and Disease. Cells. 2021;10(8):2050. [CrossRef]
  44. de la Roche J, Eberhardt MJ, Klinger AB, et al. The Molecular Basis for Species-specific Activation of Human TRPA1 Protein by Protons Involves Poorly Conserved Residues within Transmembrane Domains 5 and 6. J Biol Chem. 2013;288(28):20280-20292. [CrossRef]
  45. Almanza A, Mercado F, Vega R, Soto E. Extracellular pH modulates the voltage-dependent Ca2+ current and low threshold K+ current in hair cells. Neurochem Res. 2008;33(8):1435-1441. [CrossRef]
  46. Fluck EC, Yazici AT, Rohacs T, Moiseenkova-Bell VY. Structural basis of TRPV5 regulation by physiological and pathophysiological modulators. Cell Rep. 2022;39(4):110737. [CrossRef]
  47. Song MK, Namgung SD, Choi D, et al. Proton-enabled activation of peptide materials for biological bimodal memory. Nat Commun. 2020;11(1):5896. [CrossRef]
  48. Yao X, Klyukin K, Lu W, et al. Protonic solid-state electrochemical synapse for physical neural networks. Nat Commun. 2020;11(1):3134. [CrossRef]
  49. Davies NW, Lux HD, Morad M. Site and mechanism of activation of proton-induced sodium current in chick dorsal root ganglion neurones. J Physiol. 1988;400(1):159-187. [CrossRef]
  50. Traynelis SF, Cull-Candy SG. Pharmacological properties and H+ sensitivity of excitatory amino acid receptor channels in rat cerebellar granule neurones. J Physiol. 1991;433(1):727-763. [CrossRef]
  51. Ueno S, Nakaye T, Akaike N. Proton-induced sodium current in freshly dissociated hypothalamic neurones of the rat. J Physiol. 1992;447(1):309-327. [CrossRef]
  52. Tombaugh GC, Somjen GG. Effects of extracellular pH on voltage-gated Nae, K+ and Ca2+ currents in isolated rat CAI neurons. J Physiol. 1996;15(493 (Pt3)):719-732. [CrossRef]
  53. Willoughby D, Schwiening CJ. Electrically evoked dendritic pH transients in rat cerebellar Purkinje cells. J Physiol. 2002;544(2):487-499. [CrossRef]
  54. Beg AA, Ernstrom GG, Nix P, Davis MW, Jorgensen EM. Protons Act as a Transmitter for Muscle Contraction in C. elegans. Cell. 2008;132(1):149-160. [CrossRef]
  55. Huang J, Liu CH, Hughes SA, Postma M, Schwiening CJ, Hardie RC. Activation of TRP Channels by Protons and Phosphoinositide Depletion in Drosophila Photoreceptors. Curr Biol. 2010;20(3):189-197. [CrossRef]
  56. Ruffin VA, Salameh AI, Boron WF, Parker MD. Intracellular pH regulation by acid-base transporters in mammalian neurons. Front Physiol. 2014;5. [CrossRef]
  57. Kier L. Nerve Conduction Through Dendrites via Proton Hopping. Curr Comput Aided-Drug Des. 2017;13(1):57-59. [CrossRef]
  58. Uchitel OD, González Inchauspe C, Weissmann C. Synaptic signals mediated by protons and acid-sensing ion channels. Synapse. 2019;73(10). [CrossRef]
  59. Highstein SM, Holstein GR, Mann MA, Rabbitt RD. Evidence that protons act as neurotransmitters at vestibular hair cell–calyx afferent synapses. Proc Natl Acad Sci. 2014;111(14):5421-5426. [CrossRef]
  60. Fillafer C, Schneider MF. On the excitation of action potentials by protons and its potential implications for cholinergic transmission. Protoplasma. 2016;253(2):357-365. [CrossRef]
  61. Du J, Reznikov LR, Price MP, et al. Protons are a neurotransmitter that regulates synaptic plasticity in the lateral amygdala. Proc Natl Acad Sci. 2014;111(24):8961-8966. [CrossRef]
  62. González-Inchauspe C, Urbano FJ, Di Guilmi MN, Uchitel OD. Acid-Sensing Ion Channels Activated by Evoked Released Protons Modulate Synaptic Transmission at the Mouse Calyx of Held Synapse. J Neurosci. 2017;37(10):2589-2599. [CrossRef]
  63. Lee JW. Protonic conductor: better understanding neural resting and action potential. J Neurophysiol. 2020;124(4):1029-1044. [CrossRef]
  64. Malchow RP, Tchernookova BK, Choi J in V, Smith PJS, Kramer RH, Kreitzer MA. Review and Hypothesis: A Potential Common Link Between Glial Cells, Calcium Changes, Modulation of Synaptic Transmission, Spreading Depression, Migraine, and Epilepsy—H+. Front Cell Neurosci. 2021;15:693095. [CrossRef]
  65. Warren TJ, Van Hook MJ, Supuran CT, Thoreson WB. Sources of protons and a role for bicarbonate in inhibitory feedback from horizontal cells to cones in Ambystoma tigrinum retina: Protons and bicarbonate in horizontal cell feedback to cones. J Physiol. 2016;594(22):6661-6677. [CrossRef]
  66. Country MW, Jonz MG. Calcium dynamics and regulation in horizontal cells of the vertebrate retina: lessons from teleosts. J Neurophysiol. 2017;117(2):523-536. [CrossRef]
  67. Deng B. Alternative Models to Hodgkin-Huxley Equations. Bull Math Biol. 2017;79(6):1390-1411. [CrossRef]
  68. Catterall WA, Lenaeus MJ, Gamal El-Din TM. Structure and Pharmacology of Voltage-Gated Sodium and Calcium Channels. Annu Rev Pharmacol Toxicol. 2020;60(1):133-154. [CrossRef]
  69. Catacuzzeno L, Franciolini F. The 70-year search for the voltage-sensing mechanism of ion channels. J Physiol. 2022;600(14):3227-3247. [CrossRef]
  70. Silbering AF, Benton R. Ionotropic and metabotropic mechanisms in chemoreception: “chance or design”? EMBO Rep. 2010;11(3):173-179. [CrossRef]
  71. Liman ER, Zhang YV, Montell C. Peripheral coding of taste. Neuron. 2014;81(5):984-1000. [CrossRef]
  72. Tu YH, Cooper AJ, Teng B, et al. An evolutionarily conserved gene family encodes proton-selective ion channels. Science. 2018;359(6379):1047-1050. [CrossRef]
  73. Chang RB, Waters H, Liman ER. A proton current drives action potentials in genetically identified sour taste cells. Proc Natl Acad Sci. 2010;107(51):22320-22325. [CrossRef]
  74. Wang YY, Chang RB, Allgood SD, Silver WL, Liman ER. A TRPA1-dependent mechanism for the pungent sensation of weak acids. J Gen Physiol. 2011;137(6):493-505. [CrossRef]
  75. Huque T, Cowart BJ, Dankulich-Nagrudny L, et al. Sour Ageusia in Two Individuals Implicates Ion Channels of the ASIC and PKD Families in Human Sour Taste Perception at the Anterior Tongue. Matsunami H, ed. PLoS ONE. 2009;4(10):e7347. [CrossRef]
  76. Liman ER, Kinnamon SC. Sour taste: receptors, cells and circuits. Curr Opin Physiol. 2021;20:8-15. [CrossRef]
  77. Shah KR, Guan X, Yan J. Structural and Functional Coupling of Calcium-Activated BK Channels and Calcium-Permeable Channels Within Nanodomain Signaling Complexes. Front Physiol. 2022;12:796540. [CrossRef]
  78. Orfali R, Albanyan N. Ca2+-Sensitive Potassium Channels. Molecules. 2023;28(2):885. [CrossRef]
  79. Liccardo F, Luini A, Di Martino R. Endomembrane-Based Signaling by GPCRs and G-Proteins. Cells. 2022;11(3):528. [CrossRef]
  80. Imenez Silva PH, Wagner CA. Physiological relevance of proton-activated GPCRs. Pflüg Arch - Eur J Physiol. 2022;474(5):487-504. [CrossRef]
  81. Xue T, Do MTH, Riccio A, et al. Melanopsin signalling in mammalian iris and retina. Nature. 2011;479(7371):67-73. [CrossRef]
  82. Liu G, Badeau RM, Tanimura A, Talamo BR. Odorant receptors directly activate phospholipase C/inositol-1,4,5-trisphosphate coupled to calcium influx in Odora cells. J Neurochem. 2006;96(6):1591-1605. [CrossRef]
  83. Szebenyi SA, Ogura T, Sathyanesan A, AlMatrouk AK, Chang J, Lin W. Increases in intracellular calcium via activation of potentially multiple phospholipase C isozymes in mouse olfactory neurons. Front Cell Neurosci. 2014;8. [CrossRef]
  84. Geppetti, P, Veldhuis, NA, Lieu, TM, Bunnett, NW. G Protein-Coupled Receptors: Dynamic Machines for Signaling Pain and Itch. Neuron. 2015;88(4):635-649. [CrossRef]
  85. Deshpande DA, Wang WCH, McIlmoyle EL, et al. Bitter taste receptors on airway smooth muscle bronchodilate by localized calcium signaling and reverse obstruction. Nat Med. 2010;16(11):1299-1304. [CrossRef]
  86. Lee A, Owyang C. Sugars, Sweet Taste Receptors, and Brain Responses. Nutrients. 2017;9(7):653. [CrossRef]
  87. Ahmad R, Dalziel JE. G Protein-Coupled Receptors in Taste Physiology and Pharmacology. Front Pharmacol. 2020;11:587664. [CrossRef]
  88. Weernink O, Han L, Jakobs, KH, Schmidt, M. Dynamic phospholipid signaling by G protein-coupled receptors. Biochim Biophys Acta. 2007;1768(4):888-900. [CrossRef]
  89. Balla T. Putting G protein–coupled receptor-mediated activation of phospholipase C in the limelight. J Gen Physiol. 2010;135(2):77-80. [CrossRef]
  90. Banno Y, Nozawa Y. Characterization of partially purified phospholipase C from human platelet membranes. Biochem J. 1987;248(1):95-101. [CrossRef]
  91. Roy G, Villar LM, Lazaro I, Gonzalez M, Bootello A, Gonzalez-Porque P. Purification and properties of membrane and cytosolic phosphatidylinositol-specific phospholipases C from human spleen. J Biol Chem. 1991;266(18):11495-11501. [CrossRef]
  92. Nakamura Y, Fukami K. Regulation and physiological functions of mammalian phospholipase C. J Biochem (Tokyo). 2017;161(4):mvw094. [CrossRef]
  93. Chen W, Chen C, Yang K, et al. Arachidonic acid-induced H + and Ca 2+ increases in both the cytoplasm and nucleoplasm of rat cerebellar granule cells. J Physiol. 2001;537(2):497-510. [CrossRef]
  94. Križaj D, Mercer AJ, Thoreson WB, Barabas P. Intracellular pH modulates inner segment calcium homeostasis in vertebrate photoreceptors. Am J Physiol-Cell Physiol. 2011;300(1):C187-C197. [CrossRef]
  95. Caldwell L, Harries P, Sydlik S, Schwiening CJ. Presynaptic pH and vesicle fusion in Drosophila larvae neurones. Synapse. 2013;67(11):729-740. [CrossRef]
  96. Rossano AJ, Chouhan AK, Macleod GT. Genetically encoded pH-indicators reveal activity-dependent cytosolic acidification of Drosophila motor nerve termini in vivo: Genetic pH-indicators in motor nerve termini. J Physiol. 2013;591(7):1691-1706. [CrossRef]
  97. Zhang L, Bellve K, Fogarty K, Kobertz WR. Fluorescent Visualization of Cellular Proton Fluxes. Cell Chem Biol. 2016;23(12):1449-1457. [CrossRef]
  98. Wei D, Mei Y, Xia J, Hu H. Orai1 and Orai3 Mediate Store-Operated Calcium Entry Contributing to Neuronal Excitability in Dorsal Root Ganglion Neurons. Front Cell Neurosci. 2017;11:400. [CrossRef]
  99. Tombaugh GC, Somjen GG. Differential Sensitivity to Intracellular pH Among High- and Low-Threshold Ca 2+ Currents in Isolated Rat CA1 Neurons. J Neurophysiol. 1997;77(2):639-653. [CrossRef]
  100. Dolphin AC. Functions of Presynaptic Voltage-gated Calcium Channels. Function. 2020;2(1):zqaa027. [CrossRef]
  101. Ramachandran S, Rodgriguez S, Potcoava M, Alford S. Single Calcium Channel Nanodomains Drive Presynaptic Calcium Entry at Lamprey Reticulospinal Presynaptic Terminals. J Neurosci. 2022;42(12):2385-2403. [CrossRef]
  102. Harding EK, Zamponi GW. Central and peripheral contributions of T-type calcium channels in pain. Mol Brain. 2022;15(1):39. [CrossRef]
  103. Henrich M, Buckler KJ. Acid-evoked Ca2+ signalling in rat sensory neurones: effects of anoxia and aglycaemia. Pflüg Arch - Eur J Physiol. 2009;459(1):159-181. [CrossRef]
  104. Liu CH, Chen Z, Oliva MK, et al. Rapid Release of Ca 2+ from Endoplasmic Reticulum Mediated by Na + /Ca 2+ Exchange. J Neurosci. 2020;40(16):3152-3164. [CrossRef]
  105. Hu F, Song X, Long D. Transient receptor potential ankyrin 1 and calcium: Interactions and association with disease (Review). Exp Ther Med. 2021;22(6):1462. [CrossRef]
  106. Catterall WA, Goldin AL, Waxman SG. International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels. Pharmacol Rev. 2005;57(4):397-409. [CrossRef]
  107. Wu LG, Hamid E, Shin W, Chiang HC. Exocytosis and Endocytosis: Modes, Functions, and Coupling Mechanisms. Annu Rev Physiol. 2014;76(1):301-331. [CrossRef]
  108. Ge L, Shin W, Arpino G, et al. Sequential compound fusion and kiss-and-run mediate exo- and endocytosis in excitable cells. Sci Adv. 2022;8(24):eabm6049. [CrossRef]
  109. Grider MH, Jessu R, Kabir R. Physiology, Action Potential. Vol In: StatPearls [internet]. Treasure Island (FL): StatPearls Publishing; 2022. https://www.ncbi.nlm.nih.gov/books/NBK538143/.
  110. Kariev AM, Green ME. Protons in Gating the Kv1.2 Channel: A Calculated Set of Protonation States in Response to Polarization/Depolarization of the Channel, with the Complete Proposed Proton Path from Voltage Sensing Domain to Gate. Membranes. 2022;12(7):718. [CrossRef]
  111. Han S, Peng S, Vance J, et al. Structural dynamics determine voltage and pH gating in human voltage-gated proton channel. eLife. 2022;11:e73093. [CrossRef]
  112. Koch KW, Dell’Orco D. Protein and Signaling Networks in Vertebrate Photoreceptor Cells. Front Mol Neurosci. 2015;8. [CrossRef]
  113. Marchetta P, Rüttiger L, Hobbs AJ, Singer W, Knipper M. The role of cGMP signalling in auditory processing in health and disease. Br J Pharmacol. 2022;179(11):2378-2393. [CrossRef]
  114. Douguet D, Honoré E. Mammalian Mechanoelectrical Transduction: Structure and Function of Force-Gated Ion Channels. Cell. 2019;179(2):340-354. [CrossRef]
  115. Bavi N, Nikolaev YA, Bavi O, et al. Principles of Mechanosensing at the Membrane Interface. In: Epand RM, Ruysschaert JM, eds. The Biophysics of Cell Membranes. Vol 19. Springer Series in Biophysics. Springer Singapore; 2017:85-119. [CrossRef]
  116. Cheng YR, Jiang BY, Chen CC. Acid-sensing ion channels: dual function proteins for chemo-sensing and mechano-sensing. J Biomed Sci. 2018;25(1):46. [CrossRef]
  117. Lin HH, Ng KF, Chen TC, Tseng WY. Ligands and Beyond: Mechanosensitive Adhesion GPCRs. Pharmaceuticals. 2022;15(2):219. [CrossRef]
  118. Wei WC, Bianchi F, Wang YK, Tang MJ, Ye H, Glitsch MD. Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68). Curr Biol. 2018;28(23):3815-3823.e4. [CrossRef]
  119. Iliff, AJ, Xu, XZS. A Mechanosensitive GPCR that Detects the Bloody Force. Cell. 2018;173(3):542-544. [CrossRef]
  120. Feng, PX. The Mechanism of Hydrolysis Reaction of Adenosine Triphosphate Molecules for the Generation of Bio-Energy and its Properties in the Living Systems. Int J Pharm Anal Acta. 2017;1(1):001-008.
  121. Barbosa ML de C, Fumian MM, Miranda ALP de, Barreiro EJ, Lima LM. Therapeutic approaches for tumor necrosis factor inhibition. Braz J Pharm Sci. 2011;47(3):427-446. [CrossRef]
  122. Rybalkin SD, Hinds TR, Beavo JA. Enzyme Assays for cGMP Hydrolyzing Phosphodiesterases. In: Krieg T, Lukowski R, eds. Guanylate Cyclase and Cyclic GMP. Vol 1020. Methods in Molecular Biology. Humana Press; 2013:51-62. [CrossRef]
  123. Michaelson, DM, Angel, I. Determination of ΔpH in cholinergic synaptic vesicle. Life Sci. 1980;27(1):39-44. [CrossRef]
  124. Fuldner, HH, Stadler, H. 31P-NMR Analysis of Synaptic Vesicles. Eur J Biochem. 1982;121:519-524.
  125. Anderson RG, Orci L. A view of acidic intracellular compartments. J Cell Biol. 1988;106(3):539-543. [CrossRef]
  126. Miesenbock, G, De Angelis, DA. Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature. 1998;394(6689):192-195. [CrossRef]
  127. Egashira Y, Takase M, Watanabe S, et al. Unique pH dynamics in GABAergic synaptic vesicles illuminates the mechanism and kinetics of GABA loading. Proc Natl Acad Sci. 2016;113(38):10702-10707. [CrossRef]
  128. DeVries SH. Exocytosed Protons Feedback to Suppress the Ca2+ Current in Mammalian Cone Photoreceptors. Neuron. 2001;32(6):1107-1117. [CrossRef]
  129. Palmer MJ, Hull C, Vigh J, von Gersdorff H. Synaptic Cleft Acidification and Modulation of Short-Term Depression by Exocytosed Protons in Retinal Bipolar Cells. J Neurosci. 2003;23(36):11332-11341. [CrossRef]
  130. Ahdut-Hacohen R, Duridanova D, Meiri H, Rahamimoff R. Hydrogen ions control synaptic vesicle ion channel activity in Torpedo electromotor neurones: H + dependence of synaptic vesicle ion channels. J Physiol. 2004;556(2):347-352. [CrossRef]
  131. Kolen B, Borghans B, Kortzak D, et al. Vesicular glutamate transporters are H+-anion exchangers that operate at variable stoichiometry. Nat Commun. 2023;14(1):2723. [CrossRef]
  132. Marx MC, Billups D, Billups B. Maintaining the presynaptic glutamate supply for excitatory neurotransmission: Glutamate Recycling and Replenishment. J Neurosci Res. 2015;93(7):1031-1044. [CrossRef]
  133. Pathak D, Shields LY, Mendelsohn BA, et al. The Role of Mitochondrially Derived ATP in Synaptic Vesicle Recycling. J Biol Chem. 2015;290(37):22325-22336. [CrossRef]
  134. Eriksen J, Chang R, McGregor M, Silm K, Suzuki T, Edwards RH. Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism. Neuron. 2016;90(4):768-780. [CrossRef]
  135. Pulido, C, Ryan, TA. Synaptic vesicle pools are a major hidden resting metabolic burden of nerve terminals. Sci Adv. 2021;7(49):eabi9027. [CrossRef]
  136. Malik KU. Potentiation by Anticholinesterases of the Response of Rat Mesenteric Arteries to Sympathetic Postganglionic Nerve Stimulation. Circ Res. 1970;27(5):647-655. [CrossRef]
  137. Mike, A, Castro, NG, Albuquerque, EX. Choline and acetylcholine have similar kinetic properties of activation and desensitization on the alpha7 nicotinic receptors in rat hippocampal neurons. Brain Res. 2000;882(1-2):155-168. [CrossRef]
  138. Holzer P. Acid sensing by visceral afferent neurones: Acid sensing by visceral afferent neurones. Acta Physiol. 2011;201(1):63-75. [CrossRef]
  139. Leffler, A, Mönter, B, Koltzenburg, M. The role of the capsaicin receptor TRPV1 and acid-sensing ion channels (ASICS) in proton sensitivity of subpopulations of primary nociceptive neurons in rats and mice. Neuroscience. 2006;139(2):699-709. [CrossRef]
  140. Semtner M, Schaefer M, Pinkenburg O, Plant TD. Potentiation of TRPC5 by Protons. J Biol Chem. 2007;282(46):33868-33878. [CrossRef]
  141. Ryu S, Liu B, Yao J, Fu Q, Qin F. Uncoupling Proton Activation of Vanilloid Receptor TRPV1. J Neurosci. 2007;27(47):12797-12807. [CrossRef]
  142. Lipkin AM, Cunniff MM, Spratt PWE, Lemke SM, Bender KJ. Functional Microstructure of Ca V -Mediated Calcium Signaling in the Axon Initial Segment. J Neurosci. 2021;41(17):3764-3776. [CrossRef]
  143. Fan X, Lu Y, Du G, Liu J. Advances in the Understanding of Two-Pore Domain TASK Potassium Channels and Their Potential as Therapeutic Targets. Molecules. 2022;27(23):8296. [CrossRef]
  144. Boillat, A, Alijevic, O, Kellenberger, S. Calcium entry via TRPV1 but not ASICs induces neuropeptide release from sensory neurons. Mol Cell Neurosci. 2014;61:13-22. [CrossRef]
  145. Burke KJ, Bender KJ. Modulation of Ion Channels in the Axon: Mechanisms and Function. Front Cell Neurosci. 2019;13:221. [CrossRef]
  146. Negri S, Scolari F, Vismara M, et al. GABAA and GABAB Receptors Mediate GABA-Induced Intracellular Ca2+ Signals in Human Brain Microvascular Endothelial Cells. Cells. 2022;11(23):3860. [CrossRef]
  147. Papke, RI, Lindstrom, JM. Nicotinic acetylcholine receptors: Conventional and unconventional ligands and signaling. Neuropharmacology. 2020;15(168):108021. [CrossRef]
  148. Brown DA. Acetylcholine and cholinergic receptors. Brain Neurosci Adv. 2019;3:239821281882050. [CrossRef]
  149. Sam C, Bordoni B. Physiology, Acetylcholine. Vol In: StatPearls [Internet]. Treasure Island (FL). StatPearls Publishing; 2022. https://pubmed.ncbi.nlm.nih.gov/32491757/.
  150. Nicholson MW, Sweeney A, Pekle E, et al. Diazepam-induced loss of inhibitory synapses mediated by PLCδ/ Ca2+/calcineurin signalling downstream of GABAA receptors. Mol Psychiatry. 2018;23(9):1851-1867. [CrossRef]
  151. Ihle, Eva C., Patneau, Doris K. Modulation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid Receptor Desensitization by Extracellular Protons. Mol Pharmacol. 2000;58(6):1204-1212. [CrossRef]
  152. Mott DD, Washburn MS, Zhang S, Dingledine RJ. Subunit-Dependent Modulation of Kainate Receptors by Extracellular Protons and Polyamines. J Neurosci. 2003;23(4):1179-1188. [CrossRef]
  153. Zhang JB, Chang S, Xu P, et al. Structural Basis of the Proton Sensitivity of Human GluN1-GluN2A NMDA Receptors. Cell Rep. 2018;25(13):3582-3590.e4. [CrossRef]
  154. Dravid SM, Erreger K, Yuan H, et al. Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block: Proton sensitivity of NMDA receptor channel blockers. J Physiol. 2007;581(1):107-128. [CrossRef]
  155. Svensson E, Apergis-Schoute J, Burnstock G, Nusbaum MP, Parker D, Schiöth HB. General Principles of Neuronal Co-transmission: Insights From Multiple Model Systems. Front Neural Circuits. 2019;12:117. [CrossRef]
  156. Hunt PJ, Kochukov M, Pekarek BT, et al. Co-transmitting neurons in the lateral septal nucleus exhibit features of neurotransmitter switching. IBRO Neurosci Rep. 2022;12:390-398. [CrossRef]
Table 1. Examples of esterases, as possible sources of protons and intracellular Ca2+ spikes.
Table 1. Examples of esterases, as possible sources of protons and intracellular Ca2+ spikes.
enzyme substrate acid product reference
phospholipase A2 phosphatidylcholine arachidonic acid Sun17
phospholipase C phosphatidylinositol 4,5-bisphosphate acid IP3 Molinari, Fig.1A18
phospholipase D phosphatidylcholine phosphatidic acid Cazzolli19
inositol 5-phosphatase inositol 1,4,5-trisphosphate (IP3) phosphoric acid Majerus20
alkaline phosphatase NAADP phosphoric acid Schmid21
S1P phosphatase sphingosine 1-phosphate (S1P) phosphoric acid Wollny22
acetylcholinesterase acetylcholine acetic acid Fillafer23
Table 2. Protonated and deprotonated states of acid neurotransmitters.
Table 2. Protonated and deprotonated states of acid neurotransmitters.
Preprints 74759 i001
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
bsky
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

Privacy Settings

© 2025 MDPI (Basel, Switzerland) unless otherwise stated