Effects of ketamine and its metabolites on ion currents in differentiated hippocampal H19-7 neuronal cells and in HEK293T cells transfected with α-hslo subunit

Mei Han Huang, Kuan Hua Lin, Sheue Jiun Chen, Ai Yu Shen, Fang Tzu Wu, Sheng-Nan Wu

Research output: Contribution to journalArticle

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Abstract

Ketamine (KT), a dissociative anesthetic, is known to induce schizophrenia-like psychosis. The percentage of KT abuse has recently grown fast despite KT being a controlled drug. The mechanism of KT actions is related to the inhibition of NMDA receptors. Whether KT produces other effects on ion currents in hippocampal neurons remains unclear. In this study, we attempted to evaluate the possible effects of KT and other related compounds on ion currents in hippocampal neuron-derived H19-7 cells. This drug exerted an inhibitory effect on Ca2+-activated K+ current (IK(Ca)) in these cells with an IC50 value of 274μM. Pimaric acid (30μM) or abietic acid (30μM), known to stimulate large-conductance Ca2+-activated K+ channels, reversed KT-induced inhibition of IK(Ca). In HEK293T cells expressing α-human slowpoke, KT-induced inhibition of IK(Ca) still existed. Dehydronorketamine (300μM) had little or no effect on the IK(Ca) amplitude, while norketamine (300μM) slightly but significantly suppressed it. In inside-out configuration, KT applied to the intracellular face of the membrane did not alter single-channel conductance of large-conductance Ca2+-activated K+ (BKCa) channels; however, it did significantly reduce the probability of channel openings. Addition of KT was effective in depressing the peak amplitude of voltage-gated Na+ current. Moreover, the presence of KT was noted to enhance the amplitude of membrane electroporation-induced inward currents (IMEP) in differentiated H19-7 cells. KT-stimulated IMEP was reversed by further application of LaCl3 (100μM), but not by NMDA (30μM). The modulations by this compound of ion channels may contribute to the underlying mechanisms through which KT and its metabolites influence the electrical behavior of hippocampal neurons if similar findings occur in vivo.

Original languageEnglish
Pages (from-to)1058-1066
Number of pages9
JournalNeuroToxicology
Volume33
Issue number5
DOIs
Publication statusPublished - 2012 Oct 1

Fingerprint

Ketamine
Metabolites
Ions
Neurons
Calcium-Activated Potassium Channels
Dissociative Anesthetics
Membranes
Intracellular Membranes
Electroporation
Induced currents
N-Methylaspartate
N-Methyl-D-Aspartate Receptors
Ion Channels
Pharmaceutical Preparations
Psychotic Disorders
Inhibitory Concentration 50
Schizophrenia
Cells
Modulation

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Toxicology

Cite this

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title = "Effects of ketamine and its metabolites on ion currents in differentiated hippocampal H19-7 neuronal cells and in HEK293T cells transfected with α-hslo subunit",
abstract = "Ketamine (KT), a dissociative anesthetic, is known to induce schizophrenia-like psychosis. The percentage of KT abuse has recently grown fast despite KT being a controlled drug. The mechanism of KT actions is related to the inhibition of NMDA receptors. Whether KT produces other effects on ion currents in hippocampal neurons remains unclear. In this study, we attempted to evaluate the possible effects of KT and other related compounds on ion currents in hippocampal neuron-derived H19-7 cells. This drug exerted an inhibitory effect on Ca2+-activated K+ current (IK(Ca)) in these cells with an IC50 value of 274μM. Pimaric acid (30μM) or abietic acid (30μM), known to stimulate large-conductance Ca2+-activated K+ channels, reversed KT-induced inhibition of IK(Ca). In HEK293T cells expressing α-human slowpoke, KT-induced inhibition of IK(Ca) still existed. Dehydronorketamine (300μM) had little or no effect on the IK(Ca) amplitude, while norketamine (300μM) slightly but significantly suppressed it. In inside-out configuration, KT applied to the intracellular face of the membrane did not alter single-channel conductance of large-conductance Ca2+-activated K+ (BKCa) channels; however, it did significantly reduce the probability of channel openings. Addition of KT was effective in depressing the peak amplitude of voltage-gated Na+ current. Moreover, the presence of KT was noted to enhance the amplitude of membrane electroporation-induced inward currents (IMEP) in differentiated H19-7 cells. KT-stimulated IMEP was reversed by further application of LaCl3 (100μM), but not by NMDA (30μM). The modulations by this compound of ion channels may contribute to the underlying mechanisms through which KT and its metabolites influence the electrical behavior of hippocampal neurons if similar findings occur in vivo.",
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Effects of ketamine and its metabolites on ion currents in differentiated hippocampal H19-7 neuronal cells and in HEK293T cells transfected with α-hslo subunit. / Huang, Mei Han; Lin, Kuan Hua; Chen, Sheue Jiun; Shen, Ai Yu; Wu, Fang Tzu; Wu, Sheng-Nan.

In: NeuroToxicology, Vol. 33, No. 5, 01.10.2012, p. 1058-1066.

Research output: Contribution to journalArticle

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