Modulation of Proton-Gated Channels by Antidepressants

Nikolaev, Maxim V.; Komarova, Margarita S.; Tikhonova, Tatiana B.; Korosteleva, Anastasia S.; Potapjeva, N. N.; Tikhonov, Denis B.

doi:10.1021/acschemneuro.8b00560

Cited by 8 publications

(17 citation statements)

References 52 publications

(109 reference statements)

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“…Memantine [38] and 9-aminoacridine [39] also affect glutamate receptors as well as ASICs [31]. Other drugs included long-established antidepressants amitriptyline and tianeptine [40,41] and histamine receptor modulators imetit, dimaprit, and thioperamide [42,43]; their effects on ASICs were recently established in [34] and [35], respectively. It is important to note that in previous studies only the effects on ASIC1a and ASIC2a were examined, with ASIC3 covered very briefly in [31].…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the drug action on activation properties is notably diverse. For instance, IEM-2044 and amitriptyline have opposite effects on different channels, inducing an alkaline shift of activation on ASIC1a [32,34] and an acidic one on ASIC3, while 9AA shifts the activation to more acidic values in both cases [32]. Histamine only enhanced the activation of ASIC1a and was inactive against ASIC3 [33].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, in the present work we attempted to elucidate the mechanisms of action of hydrophobic monoamines and their guanidine analogs on ASIC3 channels. Other compounds that were found to affect ASIC1a and/or ASIC2a, such as some antidepressants [34] and histamine receptor agonists [35], were also included in the study.…”

Section: Introductionmentioning

confidence: 99%

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Hydrophobic Amines and Their Guanidine Analogues Modulate Activation and Desensitization of ASIC3

Shteinikov

Potapieva

Гмиро

et al. 2019

IJMS

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Acid-sensing ion channel 3 (ASIC3) is an important member of the acid-sensing ion channels family, which is widely expressed in the peripheral nervous system and contributes to pain sensation. ASICs are targeted by various drugs and toxins. However, mechanisms and structural determinants of ligands’ action on ASIC3 are not completely understood. In the present work we studied ASIC3 modulation by a series of “hydrophobic monoamines” and their guanidine analogs, which were previously characterized to affect other ASIC channels via multiple mechanisms. Electrophysiological analysis of action via whole-cell patch clamp method was performed using rat ASIC3 expressed in Chinese hamster ovary (CHO) cells. We found that the compounds studied inhibited ASIC3 activation by inducing acidic shift of proton sensitivity and slowed channel desensitization, which was accompanied by a decrease of the equilibrium desensitization level. The total effect of the drugs on the sustained ASIC3-mediated currents was the sum of these opposite effects. It is demonstrated that drugs’ action on activation and desensitization differed in their structural requirements, kinetics of action, and concentration and state dependencies. Taken together, these findings suggest that effects on activation and desensitization are independent and are likely mediated by drugs binding to distinct sites in ASIC3.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hydrophobic Amines and Their Guanidine Analogues Modulate Activation and Desensitization of ASIC3

Shteinikov

Potapieva

Гмиро

et al. 2019

IJMS

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“…The sequence of pH values was randomized in each cell. To reconstruct the pH-dependence curves, these data were then combined with control curve values from Nikolaev et al (2019).…”

Section: Methodsmentioning

confidence: 99%

Glutamate potentiates heterologously expressed homomeric acid‐sensing ion channel 1a

et al. 2022

Synapse

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Acid‐sensing ion channels (ASICs) participate in synaptic transmission due to the acidic content of synaptic vesicles, but their contribution to postsynaptic currents is small. This has stimulated attempts to find endogenous ASIC potentiators that could enhance ASIC‐mediated currents to physiologically relevant values. Here we demonstrate that glutamate, which serves as a neurotransmitter, potentiates recombinant ASIC1a in the submillimolar concentration range. The effect of glutamate is especially interesting as ASIC’s presence has been shown in glutamatergic synapses. At pH=6.5 glutamate had maximum potentiation of 87% with an EC50 value of 0.65 mM. The mechanism of potentiation is due to a shift of pH‐dependent activation to less acidic values, with 0.5 mM glutamate increasing pH50 from 6.04 to 6.43. Due to this mechanism, ASIC1a in glutamatergic synapses might be intrinsically potentiated. Furthermore, this effect could compensate for the inhibition of ionotropic glutamate receptors by extracellular acidification during synaptic transmission.

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“…The actions of a series of antidepressant on recombinant ASIC1a and ASIC2a, and on native ASICs in rat brain neurons was studied by Nikolaev et al (). Most of the tested compounds prevent steady‐state ASIC1a desensitization evoked by conditioning acidification to pH 7.1.…”

Section: Modulation Of Asicsmentioning

confidence: 99%

Synaptic signals mediated by protons and acid‐sensing ion channels

Uchitel

Inchauspe

Weissmann

2019

Synapse

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Extracellular pH changes may constitute significant signals for neuronal communication. During synaptic transmission, changes in pH in the synaptic cleft take place. Its role in the regulation of presynaptic Ca2+ currents through multivesicular release in ribbon‐type synapses is a proven phenomenon. In recent years, protons have been recognized as neurotransmitters that participate in neuronal communication in synapses of several regions of the CNS such as amygdala, nucleus accumbens, and brainstem. Protons are released by nerve stimulation and activate postsynaptic acid‐sensing ion channels (ASICs). Several types of ASIC channels are expressed in the peripheral and central nervous system. The influx of Ca2+ through some subtypes of ASICs, as a result of synaptic transmission, agrees with the participation of ASICs in synaptic plasticity. Pharmacological and genetical inhibition of ASIC1a results in alterations in learning, memory, and phenomena like fear and cocaine‐seeking behavior. The recognition of endogenous molecules, such as arachidonic acid, cytokines, histamine, spermine, lactate, and neuropeptides, capable of inhibiting or potentiating ASICs suggests the existence of mechanisms of synaptic modulation that have not yet been fully identified and that could be tuned by new emerging pharmacological compounds with potential therapeutic benefits.

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Modulation of Proton-Gated Channels by Antidepressants

Cited by 8 publications

References 52 publications

Hydrophobic Amines and Their Guanidine Analogues Modulate Activation and Desensitization of ASIC3

Hydrophobic Amines and Their Guanidine Analogues Modulate Activation and Desensitization of ASIC3

Glutamate potentiates heterologously expressed homomeric acid‐sensing ion channel 1a

Synaptic signals mediated by protons and acid‐sensing ion channels

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