Functional reduction of SK3-mediated currents precedes AMPA-receptor- mediated excitotoxicity in dopaminergic neurons

Bruno A. Benítez; Helen M. Belálcazar; Agustín Anastasía; Daniel T. Mamah; Charles F. Zorumski; Daniel H. Mascó; Daniel G. Herrera; Gabriel A. De Erausquin

doi:10.1016/j.neuropharm.2010.10.024

Functional reduction of SK3-mediated currents precedes AMPA-receptor- mediated excitotoxicity in dopaminergic neurons

Bruno A. Benítez, Helen M. Belálcazar, Agustín Anastasía, Daniel T. Mamah, Charles F. Zorumski, Daniel H. Mascó, Daniel G. Herrera, Gabriel A. De Erausquin

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

In primary cultures of mesencephalon small-conductance calcium-activated potassium channels (SK) are expressed in dopaminergic neurons. We characterized SK-mediated currents (I _SK) in this system and evaluated their role on homeostasis against excitotoxicity. I _SK amplitude was reduced by the glutamatergic agonist AMPA through a reduction in SK channel number in the membrane. Blockade of I _SK for 12 h with apamin or NS8593 reduced the number of dopaminergic neurons in a concentration-dependent manner. The effect of apamin was not additive to AMPA toxicity. On the other hand, two I _SK agonists, 1-EBIO and CyPPA, caused a significant reduction of spontaneous loss of dopaminergic neurons. 1-EBIO reversed the effects of both AMPA and apamin as well. Thus, I _SK influences survival and differentiation of dopaminergic neurons in vitro, and is part of protective homeostatic responses, participating in a rapidly acting negative feedback loop coupling calcium levels, neuron excitability and cellular defenses. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'.

Original language	English (US)
Pages (from-to)	1176-1186
Number of pages	11
Journal	Neuropharmacology
Volume	60
Issue number	7-8
DOIs	https://doi.org/10.1016/j.neuropharm.2010.10.024
State	Published - Jun 2011
Externally published	Yes

Keywords

1-Ebio
Apamin
CyPPA
Dopaminergic
Excitotoxicity
NS8593 AMPA
Neuroprotection
SK channels

ASJC Scopus subject areas

Cellular and Molecular Neuroscience
Pharmacology

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10.1016/j.neuropharm.2010.10.024

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@article{9308fdd3434e4facbb405c94fd1942c5,

title = "Functional reduction of SK3-mediated currents precedes AMPA-receptor- mediated excitotoxicity in dopaminergic neurons",

abstract = "In primary cultures of mesencephalon small-conductance calcium-activated potassium channels (SK) are expressed in dopaminergic neurons. We characterized SK-mediated currents (I SK) in this system and evaluated their role on homeostasis against excitotoxicity. I SK amplitude was reduced by the glutamatergic agonist AMPA through a reduction in SK channel number in the membrane. Blockade of I SK for 12 h with apamin or NS8593 reduced the number of dopaminergic neurons in a concentration-dependent manner. The effect of apamin was not additive to AMPA toxicity. On the other hand, two I SK agonists, 1-EBIO and CyPPA, caused a significant reduction of spontaneous loss of dopaminergic neurons. 1-EBIO reversed the effects of both AMPA and apamin as well. Thus, I SK influences survival and differentiation of dopaminergic neurons in vitro, and is part of protective homeostatic responses, participating in a rapidly acting negative feedback loop coupling calcium levels, neuron excitability and cellular defenses. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'.",

keywords = "1-Ebio, Apamin, CyPPA, Dopaminergic, Excitotoxicity, NS8593 AMPA, Neuroprotection, SK channels",

author = "Ben{\'i}tez, {Bruno A.} and Bel{\'a}lcazar, {Helen M.} and Agust{\'i}n Anastas{\'i}a and Mamah, {Daniel T.} and Zorumski, {Charles F.} and Masc{\'o}, {Daniel H.} and Herrera, {Daniel G.} and {De Erausquin}, {Gabriel A.}",

note = "Funding Information: The authors wish to thank Dr. Steve Mennerick for help setting up the electrophysiology experiments. We also want to acknowledge our debt of gratitude to the late Dr. Erminio Costa, without whose mentorship, encouragement, and inspiration this work would not have been possible. This work was supported by NIMH K08MH077220 award to GdE, and by NIH Neuroscience Blueprint Interdisciplinary Center Core Grant P30 NS057105 to Washington University, Washington University Department of Psychiatry Fund # 93785 , and Brigham and Women {\textquoteright} s Hospital Department of Psychiatry Fund # 016507 . ",

year = "2011",

month = jun,

doi = "10.1016/j.neuropharm.2010.10.024",

language = "English (US)",

volume = "60",

pages = "1176--1186",

journal = "Neuropharmacology",

issn = "0028-3908",

publisher = "Elsevier Ltd",

number = "7-8",

}

TY - JOUR

T1 - Functional reduction of SK3-mediated currents precedes AMPA-receptor- mediated excitotoxicity in dopaminergic neurons

AU - Benítez, Bruno A.

AU - Belálcazar, Helen M.

AU - Anastasía, Agustín

AU - Mamah, Daniel T.

AU - Zorumski, Charles F.

AU - Mascó, Daniel H.

AU - Herrera, Daniel G.

AU - De Erausquin, Gabriel A.

N1 - Funding Information: The authors wish to thank Dr. Steve Mennerick for help setting up the electrophysiology experiments. We also want to acknowledge our debt of gratitude to the late Dr. Erminio Costa, without whose mentorship, encouragement, and inspiration this work would not have been possible. This work was supported by NIMH K08MH077220 award to GdE, and by NIH Neuroscience Blueprint Interdisciplinary Center Core Grant P30 NS057105 to Washington University, Washington University Department of Psychiatry Fund # 93785 , and Brigham and Women ’ s Hospital Department of Psychiatry Fund # 016507 .

PY - 2011/6

Y1 - 2011/6

N2 - In primary cultures of mesencephalon small-conductance calcium-activated potassium channels (SK) are expressed in dopaminergic neurons. We characterized SK-mediated currents (I SK) in this system and evaluated their role on homeostasis against excitotoxicity. I SK amplitude was reduced by the glutamatergic agonist AMPA through a reduction in SK channel number in the membrane. Blockade of I SK for 12 h with apamin or NS8593 reduced the number of dopaminergic neurons in a concentration-dependent manner. The effect of apamin was not additive to AMPA toxicity. On the other hand, two I SK agonists, 1-EBIO and CyPPA, caused a significant reduction of spontaneous loss of dopaminergic neurons. 1-EBIO reversed the effects of both AMPA and apamin as well. Thus, I SK influences survival and differentiation of dopaminergic neurons in vitro, and is part of protective homeostatic responses, participating in a rapidly acting negative feedback loop coupling calcium levels, neuron excitability and cellular defenses. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'.

AB - In primary cultures of mesencephalon small-conductance calcium-activated potassium channels (SK) are expressed in dopaminergic neurons. We characterized SK-mediated currents (I SK) in this system and evaluated their role on homeostasis against excitotoxicity. I SK amplitude was reduced by the glutamatergic agonist AMPA through a reduction in SK channel number in the membrane. Blockade of I SK for 12 h with apamin or NS8593 reduced the number of dopaminergic neurons in a concentration-dependent manner. The effect of apamin was not additive to AMPA toxicity. On the other hand, two I SK agonists, 1-EBIO and CyPPA, caused a significant reduction of spontaneous loss of dopaminergic neurons. 1-EBIO reversed the effects of both AMPA and apamin as well. Thus, I SK influences survival and differentiation of dopaminergic neurons in vitro, and is part of protective homeostatic responses, participating in a rapidly acting negative feedback loop coupling calcium levels, neuron excitability and cellular defenses. This article is part of a Special Issue entitled 'Trends in Neuropharmacology: In Memory of Erminio Costa'.

KW - 1-Ebio

KW - Apamin

KW - CyPPA

KW - Dopaminergic

KW - Excitotoxicity

KW - NS8593 AMPA

KW - Neuroprotection

KW - SK channels

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U2 - 10.1016/j.neuropharm.2010.10.024

DO - 10.1016/j.neuropharm.2010.10.024

M3 - Article

C2 - 21044638

AN - SCOPUS:79954608902

SN - 0028-3908

VL - 60

SP - 1176

EP - 1186

JO - Neuropharmacology

JF - Neuropharmacology

IS - 7-8

ER -

Functional reduction of SK3-mediated currents precedes AMPA-receptor- mediated excitotoxicity in dopaminergic neurons

Abstract

Keywords

ASJC Scopus subject areas

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