The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons

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The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons. / Jehasse, Kevin; Massotte, Laurent; Hartmann, Sebastian; Vitello, Romain; Ringlet, Sofian; Vitello, Marie; Chua, Han Chow; Pless, Stephan A.; Engel, Dominique; Liégeois, Jean François; Lakaye, Bernard; Roeper, Jochen; Seutin, Vincent.

In: Neuropharmacology, Vol. 197, 108722, 2021.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Jehasse, K, Massotte, L, Hartmann, S, Vitello, R, Ringlet, S, Vitello, M, Chua, HC, Pless, SA, Engel, D, Liégeois, JF, Lakaye, B, Roeper, J & Seutin, V 2021, 'The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons', Neuropharmacology, vol. 197, 108722. https://doi.org/10.1016/j.neuropharm.2021.108722

APA

Jehasse, K., Massotte, L., Hartmann, S., Vitello, R., Ringlet, S., Vitello, M., Chua, H. C., Pless, S. A., Engel, D., Liégeois, J. F., Lakaye, B., Roeper, J., & Seutin, V. (2021). The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons. Neuropharmacology, 197, [108722]. https://doi.org/10.1016/j.neuropharm.2021.108722

Vancouver

Jehasse K, Massotte L, Hartmann S, Vitello R, Ringlet S, Vitello M et al. The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons. Neuropharmacology. 2021;197. 108722. https://doi.org/10.1016/j.neuropharm.2021.108722

Author

Jehasse, Kevin ; Massotte, Laurent ; Hartmann, Sebastian ; Vitello, Romain ; Ringlet, Sofian ; Vitello, Marie ; Chua, Han Chow ; Pless, Stephan A. ; Engel, Dominique ; Liégeois, Jean François ; Lakaye, Bernard ; Roeper, Jochen ; Seutin, Vincent. / The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons. In: Neuropharmacology. 2021 ; Vol. 197.

Bibtex

@article{4715c35c8515479f8c064278eb8fa05d,
title = "The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons",
abstract = "Although several ionic mechanisms are known to control rate and regularity of the slow pacemaker in dopamine (DA) neurons, the core mechanism of pacing is controversial. Here we tested the hypothesis that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidinium (XG), an established blocker of gating pore currents, selectively inhibits pacemaking of DA neurons. The compound inhibited all slow pacemaking DA neurons that were tested, both in the substantia nigra pars compacta, and in the ventral tegmental area. Interestingly, bursting behavior was not affected by XG. Furthermore, the drug did not affect fast pacemaking of GABAergic neurons from substantia nigra pars reticulata neurons or slow pacemaking of noradrenergic neurons. In DA neurons, current-clamp analysis revealed that XG did not appear to affect ion channels involved in the action potential. Its inhibitory effect persisted during blockade of all ion channels previously suggested to contribute to pacemaking. RNA sequencing and voltage-clamp recordings yielded no evidence for a gating pore current to underlie the conductance. However, we could isolate a small subthreshold XG-sensitive current, which was carried by both Na+ and Cl− ions. Although the molecular target of XG remains to be defined, these observations represent a step towards understanding pacemaking in DA neurons.",
keywords = "Dopaminergic neuron, Pacemaker clamp, Patch clamp, Slow pacemaker",
author = "Kevin Jehasse and Laurent Massotte and Sebastian Hartmann and Romain Vitello and Sofian Ringlet and Marie Vitello and Chua, {Han Chow} and Pless, {Stephan A.} and Dominique Engel and Li{\'e}geois, {Jean Fran{\c c}ois} and Bernard Lakaye and Jochen Roeper and Vincent Seutin",
note = "Funding Information: We thank all the members from the laboratory of Neurophysiology for the helpful discussions and their suggestions. We are also grateful to the GIGA-Genomics platform for the sequencing of mRNA. This work was supported by grants from the “ Fonds National de la Recherche Scientifique” (FNRS , Belgium) ( J.0148.19 to VS), from the “Fondation L{\'e}on Fredericq” (Belgium) (FHULF-D.MESGCAN.01-05 and “prix de l'espoir” to KJ). JFL is a Research Director of the F.R.S.-FNRS. DE and BL are Research Associates of the F.R.S.-FNRS. The salaries of KJ, RV and SR are paid by the “Fonds de la Recherche dans l{\textquoteright}Industrie et l{\textquoteright}Agriculture” (FRIA). Funding Information: We thank all the members from the laboratory of Neurophysiology for the helpful discussions and their suggestions. We are also grateful to the GIGA-Genomics platform for the sequencing of mRNA. This work was supported by grants from the ?Fonds National de la Recherche Scientifique? (FNRS, Belgium) (J.0148.19 to VS), from the ?Fondation L?on Fredericq? (Belgium) (FHULF-D.MESGCAN.01-05 and ?prix de l'espoir? to KJ). JFL is a Research Director of the F.R.S.-FNRS. DE and BL are Research Associates of the F.R.S.-FNRS. The salaries of KJ, RV and SR are paid by the ?Fonds de la Recherche dans l'Industrie et l'Agriculture? (FRIA). Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",
year = "2021",
doi = "10.1016/j.neuropharm.2021.108722",
language = "English",
volume = "197",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Pergamon Press",

}

RIS

TY - JOUR

T1 - The gating pore blocker 1-(2,4-xylyl)guanidinium selectively inhibits pacemaking of midbrain dopaminergic neurons

AU - Jehasse, Kevin

AU - Massotte, Laurent

AU - Hartmann, Sebastian

AU - Vitello, Romain

AU - Ringlet, Sofian

AU - Vitello, Marie

AU - Chua, Han Chow

AU - Pless, Stephan A.

AU - Engel, Dominique

AU - Liégeois, Jean François

AU - Lakaye, Bernard

AU - Roeper, Jochen

AU - Seutin, Vincent

N1 - Funding Information: We thank all the members from the laboratory of Neurophysiology for the helpful discussions and their suggestions. We are also grateful to the GIGA-Genomics platform for the sequencing of mRNA. This work was supported by grants from the “ Fonds National de la Recherche Scientifique” (FNRS , Belgium) ( J.0148.19 to VS), from the “Fondation Léon Fredericq” (Belgium) (FHULF-D.MESGCAN.01-05 and “prix de l'espoir” to KJ). JFL is a Research Director of the F.R.S.-FNRS. DE and BL are Research Associates of the F.R.S.-FNRS. The salaries of KJ, RV and SR are paid by the “Fonds de la Recherche dans l’Industrie et l’Agriculture” (FRIA). Funding Information: We thank all the members from the laboratory of Neurophysiology for the helpful discussions and their suggestions. We are also grateful to the GIGA-Genomics platform for the sequencing of mRNA. This work was supported by grants from the ?Fonds National de la Recherche Scientifique? (FNRS, Belgium) (J.0148.19 to VS), from the ?Fondation L?on Fredericq? (Belgium) (FHULF-D.MESGCAN.01-05 and ?prix de l'espoir? to KJ). JFL is a Research Director of the F.R.S.-FNRS. DE and BL are Research Associates of the F.R.S.-FNRS. The salaries of KJ, RV and SR are paid by the ?Fonds de la Recherche dans l'Industrie et l'Agriculture? (FRIA). Publisher Copyright: © 2021 Elsevier Ltd

PY - 2021

Y1 - 2021

N2 - Although several ionic mechanisms are known to control rate and regularity of the slow pacemaker in dopamine (DA) neurons, the core mechanism of pacing is controversial. Here we tested the hypothesis that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidinium (XG), an established blocker of gating pore currents, selectively inhibits pacemaking of DA neurons. The compound inhibited all slow pacemaking DA neurons that were tested, both in the substantia nigra pars compacta, and in the ventral tegmental area. Interestingly, bursting behavior was not affected by XG. Furthermore, the drug did not affect fast pacemaking of GABAergic neurons from substantia nigra pars reticulata neurons or slow pacemaking of noradrenergic neurons. In DA neurons, current-clamp analysis revealed that XG did not appear to affect ion channels involved in the action potential. Its inhibitory effect persisted during blockade of all ion channels previously suggested to contribute to pacemaking. RNA sequencing and voltage-clamp recordings yielded no evidence for a gating pore current to underlie the conductance. However, we could isolate a small subthreshold XG-sensitive current, which was carried by both Na+ and Cl− ions. Although the molecular target of XG remains to be defined, these observations represent a step towards understanding pacemaking in DA neurons.

AB - Although several ionic mechanisms are known to control rate and regularity of the slow pacemaker in dopamine (DA) neurons, the core mechanism of pacing is controversial. Here we tested the hypothesis that pacemaking of SNc DA neurons is enabled by an unconventional conductance. We found that 1-(2,4-xylyl)guanidinium (XG), an established blocker of gating pore currents, selectively inhibits pacemaking of DA neurons. The compound inhibited all slow pacemaking DA neurons that were tested, both in the substantia nigra pars compacta, and in the ventral tegmental area. Interestingly, bursting behavior was not affected by XG. Furthermore, the drug did not affect fast pacemaking of GABAergic neurons from substantia nigra pars reticulata neurons or slow pacemaking of noradrenergic neurons. In DA neurons, current-clamp analysis revealed that XG did not appear to affect ion channels involved in the action potential. Its inhibitory effect persisted during blockade of all ion channels previously suggested to contribute to pacemaking. RNA sequencing and voltage-clamp recordings yielded no evidence for a gating pore current to underlie the conductance. However, we could isolate a small subthreshold XG-sensitive current, which was carried by both Na+ and Cl− ions. Although the molecular target of XG remains to be defined, these observations represent a step towards understanding pacemaking in DA neurons.

KW - Dopaminergic neuron

KW - Pacemaker clamp

KW - Patch clamp

KW - Slow pacemaker

U2 - 10.1016/j.neuropharm.2021.108722

DO - 10.1016/j.neuropharm.2021.108722

M3 - Journal article

C2 - 34273387

AN - SCOPUS:85110683629

VL - 197

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

M1 - 108722

ER -

ID: 286501763