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 journal › Journal article › Research › peer-review
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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