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Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels

Introduction: In addition to members of the family of Na(+)/Cl(−) dependent monoamine transporters, organic cation transporters (OCTs), in particular OCT3, as well as the plasma membrane monoamine transporter (PMAT) may contribute to neuronal reuptake of according neurotransmitters. As opposed to th...

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Autores principales: Haar, Gabriele, Hrachova, Katsiaryna, Wagner, Tanja, Boehm, Stefan, Schicker, Klaus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10597664/
https://www.ncbi.nlm.nih.gov/pubmed/37881182
http://dx.doi.org/10.3389/fphar.2023.1276100
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author Haar, Gabriele
Hrachova, Katsiaryna
Wagner, Tanja
Boehm, Stefan
Schicker, Klaus
author_facet Haar, Gabriele
Hrachova, Katsiaryna
Wagner, Tanja
Boehm, Stefan
Schicker, Klaus
author_sort Haar, Gabriele
collection PubMed
description Introduction: In addition to members of the family of Na(+)/Cl(−) dependent monoamine transporters, organic cation transporters (OCTs), in particular OCT3, as well as the plasma membrane monoamine transporter (PMAT) may contribute to neuronal reuptake of according neurotransmitters. As opposed to the numerous blockers of monoamine transporters, only a very limited number of specific blockers of OCT3 and PMAT are available. In fact, decynium-22 is the only blocking agent with micromolar affinities for both transport proteins, and this molecule is frequently used to establish roles of OCT3 and/or PMAT as targets for antidepressant drugs and psychostimulants, respectively. Methods/Results: To test for a function of these transporters in the sympathetic nervous system, uptake and release of [3H]1-methyl-4-phenylpyridinium (MPP(+)) was investigated in primary cultures of rat superior cervical ganglia. Uptake was reduced by cocaine or desipramine, blockers of the noradrenaline transporter, by about 70% and by corticosterone or β-estradiol, blockers of OCT3, by about 30%; decynium-22 achieved complete inhibition of uptake with half maximal effects at 3 μM. Depolarization dependent release was enhanced by corticosterone or β-estradiol, but reduced by decynium-22. As the latter effect is unlikely to be related to actions at OCT3 and/or PMAT, electrophysiological recordings were performed to reveal that decynium-22 inhibits action potential firing and currents through voltage activated calcium channels in superior cervical ganglion neurons. Discussion: These results demonstrate that decynium-22 can impair exocytotic neurotransmitter release by interfering with several types of ion channels. Such transporter-independent effects of decynium-22 that my interfere with basic neuronal functions need to be considered when interpreting results obtained with decynium-22 as prototypic inhibitor of transmitter reuptake via OCT3 and/or PMAT.
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spelling pubmed-105976642023-10-25 Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels Haar, Gabriele Hrachova, Katsiaryna Wagner, Tanja Boehm, Stefan Schicker, Klaus Front Pharmacol Pharmacology Introduction: In addition to members of the family of Na(+)/Cl(−) dependent monoamine transporters, organic cation transporters (OCTs), in particular OCT3, as well as the plasma membrane monoamine transporter (PMAT) may contribute to neuronal reuptake of according neurotransmitters. As opposed to the numerous blockers of monoamine transporters, only a very limited number of specific blockers of OCT3 and PMAT are available. In fact, decynium-22 is the only blocking agent with micromolar affinities for both transport proteins, and this molecule is frequently used to establish roles of OCT3 and/or PMAT as targets for antidepressant drugs and psychostimulants, respectively. Methods/Results: To test for a function of these transporters in the sympathetic nervous system, uptake and release of [3H]1-methyl-4-phenylpyridinium (MPP(+)) was investigated in primary cultures of rat superior cervical ganglia. Uptake was reduced by cocaine or desipramine, blockers of the noradrenaline transporter, by about 70% and by corticosterone or β-estradiol, blockers of OCT3, by about 30%; decynium-22 achieved complete inhibition of uptake with half maximal effects at 3 μM. Depolarization dependent release was enhanced by corticosterone or β-estradiol, but reduced by decynium-22. As the latter effect is unlikely to be related to actions at OCT3 and/or PMAT, electrophysiological recordings were performed to reveal that decynium-22 inhibits action potential firing and currents through voltage activated calcium channels in superior cervical ganglion neurons. Discussion: These results demonstrate that decynium-22 can impair exocytotic neurotransmitter release by interfering with several types of ion channels. Such transporter-independent effects of decynium-22 that my interfere with basic neuronal functions need to be considered when interpreting results obtained with decynium-22 as prototypic inhibitor of transmitter reuptake via OCT3 and/or PMAT. Frontiers Media S.A. 2023-10-10 /pmc/articles/PMC10597664/ /pubmed/37881182 http://dx.doi.org/10.3389/fphar.2023.1276100 Text en Copyright © 2023 Haar, Hrachova, Wagner, Boehm and Schicker. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Haar, Gabriele
Hrachova, Katsiaryna
Wagner, Tanja
Boehm, Stefan
Schicker, Klaus
Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels
title Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels
title_full Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels
title_fullStr Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels
title_full_unstemmed Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels
title_short Impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels
title_sort impairment of exocytotic transmitter release by decynium-22 through an inhibition of ion channels
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10597664/
https://www.ncbi.nlm.nih.gov/pubmed/37881182
http://dx.doi.org/10.3389/fphar.2023.1276100
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