Determinants of action of hydrophobic amines on ASIC1a and ASIC2a

Nagaeva, Elina; Potapieva, Natalia N.; Nikolaev, Maxim V.; Гмиро, В. Е.; Magazanik, L. G.; Tikhonov, Denis B.

doi:10.1016/j.ejphar.2016.06.013

Cited by 13 publications

(10 citation statements)

References 48 publications

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“…We previously found that rather simple amine-containing compounds (Figure a) affect ASICs in a subunit-specific manner, leading to a channel block and/or a shift of pH dependence of activation and steady-state desensitization (SSD). − The NMDAR channel blocker memantine and the H4R antagonist A943931 block the pore of ASIC1a homomers as well as previously described amiloride, , diminazene, , and 4-aminopyridine . Another NMDAR channel blocker, 9-aminoacridine, causes ASIC1a inhibition by shifting the pH dependence of activation to more acidic values.…”

Section: Introductionmentioning

confidence: 66%

“…Histamine shifts the pH dependence in the opposite direction, resulting in a potentiating effect . Both histamine and memantine reduce SSD and allow ASIC1a to function under conditions of acidification. , Phenylcyclohexyl derivatives IEM-1921 and IEM-2044 potentiate ASIC2a, with the latter compound also having a potentiating effect on ASIC1a …”

Section: Introductionmentioning

confidence: 99%

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Modulation of Proton-Gated Channels by Antidepressants

Nikolaev

Komarova

Tikhonova

et al. 2018

ACS Chem. Neurosci.

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The chemical structures of some antidepressants are similar to those of recently described amine-containing ligands of acid-sensing ion channels (ASICs). ASICs are expressed in brain neurons and participate in numerous CNS functions. As such, they can be related to antidepressant action or side effects. We therefore studied the actions of a series of antidepressants on recombinant ASIC1a and ASIC2a and on native ASICs in rat brain neurons. Most of the tested compounds prevented steady-state ASIC1a desensitization evoked by conditioning acidification to pH 7.1. Amitriptyline also potentiated ASIC1a responses evoked by pH drops from 7.4 to 6.5. We conclude that amitriptyline has a twofold effect: it shifts activation to less acidic values while also shifting steady-state desensitization to more acidic values. Chlorpromazine, desipramine, amitriptyline, fluoxetine, and atomoxetine potentiated ASIC2a response. Tianeptine caused strong inhibition of ASIC2a. Both potentiation and inhibition of ASIC2a were accompanied by the slowdown of desensitization, suggesting distinct mechanisms of action on activation and desensitization. In experiments on native heteromeric ASICs, tianeptine and amitriptyline demonstrated the same modes of action as on ASIC2a although with reduced potency.

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Section: Introductionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Modulation of Proton-Gated Channels by Antidepressants

Nikolaev

Komarova

Tikhonova

et al. 2018

ACS Chem. Neurosci.

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“…Histamine (30 μM), was found to selectively potentiate ASIC1a homomers expressed in heterologous systems. Its action is particularly pronounced at minor acidifications, which cause small responses (Nagaeva et al, ). The potentiation effect of histamine on ASIC1a currents in ex vivo stem brain slices was recently demonstrated by our group (Figure ) (González Inchauspe, Gobetto, & Uchitel, in press).…”

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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“…Further structural and functional analysis [63] has identified potentiators of ASIC1a. We found that incorporation of a methylene group between the phenylcyclohexyl ring and the amino group in IEM-1921 conferred weak potentiation, while insertion of the second group enhanced potentiation (compound IEM-2044).…”

Section: Asic1a Ligandsmentioning

confidence: 99%

Ligands of Acid-Sensing Ion Channel 1a: Mechanisms of Action and Binding Sites

Tikhonov

Nagaeva

2019

Acta Naturae

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The proton-gated cationic channels belonging to the ASIC family are widely distributed in the central nervous system of vertebrates and play an important role in several physiological and pathological processes. ASIC1a are most sensitive to acidification of the external medium, which is the reason for the current interest in their function and pharmacology. Recently, the list of ASIC1a ligands has been rapidly expanding. It includes inorganic cations, a large number of synthetic and endogenous small molecules, and peptide toxins. The information on the mechanisms of action and the binding sites of the ligands comes from electrophysiological, mutational and structural studies. In the present review, we attempt to present a systematic view of the complex pattern of interactions between ligands and ASIC1a.

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Determinants of action of hydrophobic amines on ASIC1a and ASIC2a

Cited by 13 publications

References 48 publications

Modulation of Proton-Gated Channels by Antidepressants

Modulation of Proton-Gated Channels by Antidepressants

Synaptic signals mediated by protons and acid‐sensing ion channels

Ligands of Acid-Sensing Ion Channel 1a: Mechanisms of Action and Binding Sites

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