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Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects
Although the potent anti-parkinsonian action of the atypical D(1)-like receptor agonist SKF83959 has been attributed to the selective activation of phosphoinositol(PI)-linked D(1) receptor, whereas the mechanism underlying its potent neuroprotective effect is not fully understood. In the present stu...
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948503/ https://www.ncbi.nlm.nih.gov/pubmed/20957037 http://dx.doi.org/10.1371/journal.pone.0013118 |
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author | Chu, Hong-Yuan Gu, Qinhua Jin, Guo-Zhang Hu, Guo-Yuan Zhen, Xuechu |
author_facet | Chu, Hong-Yuan Gu, Qinhua Jin, Guo-Zhang Hu, Guo-Yuan Zhen, Xuechu |
author_sort | Chu, Hong-Yuan |
collection | PubMed |
description | Although the potent anti-parkinsonian action of the atypical D(1)-like receptor agonist SKF83959 has been attributed to the selective activation of phosphoinositol(PI)-linked D(1) receptor, whereas the mechanism underlying its potent neuroprotective effect is not fully understood. In the present study, the actions of SKF83959 on neuronal membrane potential and neuronal excitability were investigated in CA1 pyramidal neurons of rat hippocampal slices. SKF83959 (10–100 µM) caused a concentration-dependent depolarization, associated with a reduction of input resistance in CA1 pyramidal neurons. The depolarization was blocked neither by antagonists for D(1), D(2), 5-HT(2A/2C) receptors and α(1)-adrenoceptor, nor by intracellular dialysis of GDP-β-S. However, the specific HCN channel blocker ZD7288 (10 µM) antagonized both the depolarization and reduction of input resistance caused by SKF83959. In voltage-clamp experiments, SKF83959 (10–100 µM) caused a concentration-dependent increase of Ih current in CA1 pyramidal neurons, which was independent of D(1) receptor activation. Moreover, SKF83959 (50 µM) caused a 6 mV positive shift in the activation curve of Ih and significantly accelerated the activation of Ih current. In addition, SKF83959 also reduced the neuronal excitability of CA1 pyramidal neurons, which was manifested by the decrease in the number and amplitude of action potentials evoked by depolarizing currents, and by the increase of firing threshold and rhoebase current. The above results suggest that SKF83959 increased Ih current through a D(1) receptor-independent mechanism, which led to the depolarization of hippocampal CA1 pyramidal neurons. These findings provide a novel mechanism for the drug's neuroprotective effects, which may contributes to its therapeutic benefits in Parkinson's disease. |
format | Text |
id | pubmed-2948503 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29485032010-10-18 Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects Chu, Hong-Yuan Gu, Qinhua Jin, Guo-Zhang Hu, Guo-Yuan Zhen, Xuechu PLoS One Research Article Although the potent anti-parkinsonian action of the atypical D(1)-like receptor agonist SKF83959 has been attributed to the selective activation of phosphoinositol(PI)-linked D(1) receptor, whereas the mechanism underlying its potent neuroprotective effect is not fully understood. In the present study, the actions of SKF83959 on neuronal membrane potential and neuronal excitability were investigated in CA1 pyramidal neurons of rat hippocampal slices. SKF83959 (10–100 µM) caused a concentration-dependent depolarization, associated with a reduction of input resistance in CA1 pyramidal neurons. The depolarization was blocked neither by antagonists for D(1), D(2), 5-HT(2A/2C) receptors and α(1)-adrenoceptor, nor by intracellular dialysis of GDP-β-S. However, the specific HCN channel blocker ZD7288 (10 µM) antagonized both the depolarization and reduction of input resistance caused by SKF83959. In voltage-clamp experiments, SKF83959 (10–100 µM) caused a concentration-dependent increase of Ih current in CA1 pyramidal neurons, which was independent of D(1) receptor activation. Moreover, SKF83959 (50 µM) caused a 6 mV positive shift in the activation curve of Ih and significantly accelerated the activation of Ih current. In addition, SKF83959 also reduced the neuronal excitability of CA1 pyramidal neurons, which was manifested by the decrease in the number and amplitude of action potentials evoked by depolarizing currents, and by the increase of firing threshold and rhoebase current. The above results suggest that SKF83959 increased Ih current through a D(1) receptor-independent mechanism, which led to the depolarization of hippocampal CA1 pyramidal neurons. These findings provide a novel mechanism for the drug's neuroprotective effects, which may contributes to its therapeutic benefits in Parkinson's disease. Public Library of Science 2010-10-01 /pmc/articles/PMC2948503/ /pubmed/20957037 http://dx.doi.org/10.1371/journal.pone.0013118 Text en Chu et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Chu, Hong-Yuan Gu, Qinhua Jin, Guo-Zhang Hu, Guo-Yuan Zhen, Xuechu Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects |
title | Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects |
title_full | Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects |
title_fullStr | Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects |
title_full_unstemmed | Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects |
title_short | Electrophysiological Effects of SKF83959 on Hippocampal CA1 Pyramidal Neurons: Potential Mechanisms for the Drug's Neuroprotective Effects |
title_sort | electrophysiological effects of skf83959 on hippocampal ca1 pyramidal neurons: potential mechanisms for the drug's neuroprotective effects |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948503/ https://www.ncbi.nlm.nih.gov/pubmed/20957037 http://dx.doi.org/10.1371/journal.pone.0013118 |
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