Galantamine inhibits slowly inactivating K+ currents with a dual dose-response relationship in differentiated N1E-115 cells and in CA1 neurones

M.I. Vicente, P.F. Costa, P.A. Lima

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Abstract

Galantamine, one of the major drugs used in Alzheimer's disease therapy, is a relatively weak acetylcholinesterase inhibitor and an allosteric potentiating ligand of nicotinic acetylcholine receptors. However, a role in the control of excitability has also been attributed to galantamine via modulation of K+ currents in central neurones. To further investigate the effect of galantamine on voltage-activated K+ currents, we performed whole-cell voltage-clamp recordings in differentiated neuroblastoma N1E-115 cells and in dissociated rat CA1 neurones. In both cell models, one can identify two main voltage-activated K+ current components: a relatively fast inactivating component (Ifast; time constant~hundred milliseconds) and a slowly inactivating one (Islow; time constant~1s). We show that galantamine (1pM-300μM) inhibits selectively Islow, exhibiting a dual dose-response relationship, in both differentiated N1E-115 cells and CA1 neurones. We also demonstrate that, in contrast with what was previously reported, galantamine-induced inhibition is not due to a shift on the steady-state inactivation and activation curves. Additionally, we characterized a methodological artefact that affects voltage-dependence as a function of time in whole-cell configuration, observed in both cell models. By resolving an inhibitory role on K+ currents in a non-central neuronal system and in hippocampal neurones, we are attributing a widespread role of galantamine on the modulation of cell excitability. The present results are relevant in the clinical context, since the effects at low dosages suggest that galantamine-induced K+ current inhibition may contribute to the efficiency of galantamine in the treatment of Alzheimer's disease. © 2010 Elsevier B.V.
Original languageEnglish
Pages (from-to)16-25
Number of pages10
JournalEuropean Journal Of Pharmacology
Volume634
Issue number1-3
DOIs
Publication statusPublished - 2010

Fingerprint

Galantamine
Neurons
Alzheimer Disease
Cholinesterase Inhibitors
Nicotinic Receptors
Neuroblastoma
Artifacts
Ligands
Efficiency

Keywords

  • Acetylcholinesterase inhibitor
  • Alzheimer's disease
  • Galantamine
  • Hippocampus
  • Neuroblastoma
  • Voltage-clamp artefact
  • galantamine
  • voltage gated potassium channel
  • potassium channel
  • potassium channel blocking agent
  • animal cell
  • animal experiment
  • article
  • cell differentiation
  • controlled study
  • dose response
  • electrophysiology
  • hippocampus
  • mouse
  • nerve cell
  • nerve cell excitability
  • neuroblastoma cell
  • nonhuman
  • potassium current
  • priority journal
  • pyramidal nerve cell
  • rat
  • steady state
  • voltage clamp
  • action potential
  • animal
  • comparative study
  • cytology
  • drug effects
  • hippocampal CA1 region
  • physiology
  • tumor cell line
  • Action Potentials
  • Animals
  • CA1 Region, Hippocampal
  • Cell Differentiation
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Mice
  • Neurons
  • Potassium Channel Blockers
  • Potassium Channels
  • Rats

Cite this

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title = "Galantamine inhibits slowly inactivating K+ currents with a dual dose-response relationship in differentiated N1E-115 cells and in CA1 neurones",
abstract = "Galantamine, one of the major drugs used in Alzheimer's disease therapy, is a relatively weak acetylcholinesterase inhibitor and an allosteric potentiating ligand of nicotinic acetylcholine receptors. However, a role in the control of excitability has also been attributed to galantamine via modulation of K+ currents in central neurones. To further investigate the effect of galantamine on voltage-activated K+ currents, we performed whole-cell voltage-clamp recordings in differentiated neuroblastoma N1E-115 cells and in dissociated rat CA1 neurones. In both cell models, one can identify two main voltage-activated K+ current components: a relatively fast inactivating component (Ifast; time constant~hundred milliseconds) and a slowly inactivating one (Islow; time constant~1s). We show that galantamine (1pM-300μM) inhibits selectively Islow, exhibiting a dual dose-response relationship, in both differentiated N1E-115 cells and CA1 neurones. We also demonstrate that, in contrast with what was previously reported, galantamine-induced inhibition is not due to a shift on the steady-state inactivation and activation curves. Additionally, we characterized a methodological artefact that affects voltage-dependence as a function of time in whole-cell configuration, observed in both cell models. By resolving an inhibitory role on K+ currents in a non-central neuronal system and in hippocampal neurones, we are attributing a widespread role of galantamine on the modulation of cell excitability. The present results are relevant in the clinical context, since the effects at low dosages suggest that galantamine-induced K+ current inhibition may contribute to the efficiency of galantamine in the treatment of Alzheimer's disease. {\circledC} 2010 Elsevier B.V.",
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author = "M.I. Vicente and P.F. Costa and P.A. Lima",
year = "2010",
doi = "10.1016/j.ejphar.2010.02.021",
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journal = "European Journal Of Pharmacology",
issn = "0014-2999",
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TY - JOUR

T1 - Galantamine inhibits slowly inactivating K+ currents with a dual dose-response relationship in differentiated N1E-115 cells and in CA1 neurones

AU - Vicente, M.I.

AU - Costa, P.F.

AU - Lima, P.A.

PY - 2010

Y1 - 2010

N2 - Galantamine, one of the major drugs used in Alzheimer's disease therapy, is a relatively weak acetylcholinesterase inhibitor and an allosteric potentiating ligand of nicotinic acetylcholine receptors. However, a role in the control of excitability has also been attributed to galantamine via modulation of K+ currents in central neurones. To further investigate the effect of galantamine on voltage-activated K+ currents, we performed whole-cell voltage-clamp recordings in differentiated neuroblastoma N1E-115 cells and in dissociated rat CA1 neurones. In both cell models, one can identify two main voltage-activated K+ current components: a relatively fast inactivating component (Ifast; time constant~hundred milliseconds) and a slowly inactivating one (Islow; time constant~1s). We show that galantamine (1pM-300μM) inhibits selectively Islow, exhibiting a dual dose-response relationship, in both differentiated N1E-115 cells and CA1 neurones. We also demonstrate that, in contrast with what was previously reported, galantamine-induced inhibition is not due to a shift on the steady-state inactivation and activation curves. Additionally, we characterized a methodological artefact that affects voltage-dependence as a function of time in whole-cell configuration, observed in both cell models. By resolving an inhibitory role on K+ currents in a non-central neuronal system and in hippocampal neurones, we are attributing a widespread role of galantamine on the modulation of cell excitability. The present results are relevant in the clinical context, since the effects at low dosages suggest that galantamine-induced K+ current inhibition may contribute to the efficiency of galantamine in the treatment of Alzheimer's disease. © 2010 Elsevier B.V.

AB - Galantamine, one of the major drugs used in Alzheimer's disease therapy, is a relatively weak acetylcholinesterase inhibitor and an allosteric potentiating ligand of nicotinic acetylcholine receptors. However, a role in the control of excitability has also been attributed to galantamine via modulation of K+ currents in central neurones. To further investigate the effect of galantamine on voltage-activated K+ currents, we performed whole-cell voltage-clamp recordings in differentiated neuroblastoma N1E-115 cells and in dissociated rat CA1 neurones. In both cell models, one can identify two main voltage-activated K+ current components: a relatively fast inactivating component (Ifast; time constant~hundred milliseconds) and a slowly inactivating one (Islow; time constant~1s). We show that galantamine (1pM-300μM) inhibits selectively Islow, exhibiting a dual dose-response relationship, in both differentiated N1E-115 cells and CA1 neurones. We also demonstrate that, in contrast with what was previously reported, galantamine-induced inhibition is not due to a shift on the steady-state inactivation and activation curves. Additionally, we characterized a methodological artefact that affects voltage-dependence as a function of time in whole-cell configuration, observed in both cell models. By resolving an inhibitory role on K+ currents in a non-central neuronal system and in hippocampal neurones, we are attributing a widespread role of galantamine on the modulation of cell excitability. The present results are relevant in the clinical context, since the effects at low dosages suggest that galantamine-induced K+ current inhibition may contribute to the efficiency of galantamine in the treatment of Alzheimer's disease. © 2010 Elsevier B.V.

KW - Acetylcholinesterase inhibitor

KW - Alzheimer's disease

KW - Galantamine

KW - Hippocampus

KW - Neuroblastoma

KW - Voltage-clamp artefact

KW - galantamine

KW - voltage gated potassium channel

KW - potassium channel

KW - potassium channel blocking agent

KW - animal cell

KW - animal experiment

KW - article

KW - cell differentiation

KW - controlled study

KW - dose response

KW - electrophysiology

KW - hippocampus

KW - mouse

KW - nerve cell

KW - nerve cell excitability

KW - neuroblastoma cell

KW - nonhuman

KW - potassium current

KW - priority journal

KW - pyramidal nerve cell

KW - rat

KW - steady state

KW - voltage clamp

KW - action potential

KW - animal

KW - comparative study

KW - cytology

KW - drug effects

KW - hippocampal CA1 region

KW - physiology

KW - tumor cell line

KW - Action Potentials

KW - Animals

KW - CA1 Region, Hippocampal

KW - Cell Differentiation

KW - Cell Line, Tumor

KW - Dose-Response Relationship, Drug

KW - Mice

KW - Neurons

KW - Potassium Channel Blockers

KW - Potassium Channels

KW - Rats

U2 - 10.1016/j.ejphar.2010.02.021

DO - 10.1016/j.ejphar.2010.02.021

M3 - Article

VL - 634

SP - 16

EP - 25

JO - European Journal Of Pharmacology

JF - European Journal Of Pharmacology

SN - 0014-2999

IS - 1-3

ER -