PortalPublikationenActivation of GABA(A) receptors by guanidinoacetate

Activation of GABA(A) receptors by guanidinoacetate

Standard

Activation of GABA(A) receptors by guanidinoacetate : a novel pathophysiological mechanism. / Neu, Axel; Neuhoff, Henrike; Trube, Gerhard; Fehr, Susanne; Ullrich, Kurt; Roeper, Jochen; Isbrandt, Dirk.

in: NEUROBIOL DIS, Jahrgang 11, Nr. 2, 01.11.2002, S. 298-307.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Neu, A, Neuhoff, H, Trube, G, Fehr, S, Ullrich, K, Roeper, J & Isbrandt, D 2002, 'Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism', NEUROBIOL DIS, Jg. 11, Nr. 2, S. 298-307.

APA

Neu, A., Neuhoff, H., Trube, G., Fehr, S., Ullrich, K., Roeper, J., & Isbrandt, D. (2002). Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism. NEUROBIOL DIS, 11(2), 298-307.

Vancouver

Neu A, Neuhoff H, Trube G, Fehr S, Ullrich K, Roeper J et al. Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism. NEUROBIOL DIS. 2002 Nov 1;11(2):298-307.

Bibtex

@article{129396f1874545c38b821945a9a6629e,
title = "Activation of GABA(A) receptors by guanidinoacetate: a novel pathophysiological mechanism",
abstract = "Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. The disease occurs in early life with developmental delay or arrest and several neurological symptoms, e.g., seizures and dyskinesia. Both the deficiency of high-energy phosphates in neurons and the neurotoxic action of the accumulated metabolite guanidinoacetate (GAA) are candidate mechanisms for the pathophysiology of this disease. To examine a potential role of GAA accumulation, we analyzed the electrophysiological responses of neurons induced by GAA application in primary culture and acute murine brain slices. GAA evoked picrotoxin- and bicuculline-sensitive GABA(A) receptor-mediated chloride currents with an EC(50) of 167 microM in cortical neurons. Pathophysiologically relevant GAA concentrations hyperpolarized globus pallidus neurons and reduced their spontaneous spike frequency with an EC(50) of 15.1 microM. Furthermore, GAA acted as a partial agonist at heterologously expressed GABA(A) but not GABA(B) receptors. The interaction of GAA with neuronal GABA(A) receptors represents a candidate mechanism explaining neurological dysfunction in GAMT deficiency.",
keywords = "Animals, Animals, Newborn, Bicyclo Compounds, Heterocyclic, Binding Sites, Brain, Brain Diseases, Metabolic, Inborn, CHO Cells, Chloride Channels, Creatine, Cricetinae, Female, GABA Antagonists, GABA-A Receptor Agonists, GABA-A Receptor Antagonists, GABA-B Receptor Agonists, GABA-B Receptor Antagonists, Globus Pallidus, Glycine, Guanidinoacetate N-Methyltransferase, Membrane Potentials, Methyltransferases, Mice, Mice, Inbred C57BL, Neurons, Oocytes, Receptors, GABA-A, Receptors, GABA-B, Recombinant Fusion Proteins, Sulfur Radioisotopes, Xenopus",
author = "Axel Neu and Henrike Neuhoff and Gerhard Trube and Susanne Fehr and Kurt Ullrich and Jochen Roeper and Dirk Isbrandt",
year = "2002",
month = nov,
day = "1",
language = "English",
volume = "11",
pages = "298--307",
journal = "NEUROBIOL DIS",
issn = "0969-9961",
publisher = "Academic Press Inc.",
number = "2",

}

RIS

TY - JOUR

T1 - Activation of GABA(A) receptors by guanidinoacetate

T2 - a novel pathophysiological mechanism

AU - Neu, Axel

AU - Neuhoff, Henrike

AU - Trube, Gerhard

AU - Fehr, Susanne

AU - Ullrich, Kurt

AU - Roeper, Jochen

AU - Isbrandt, Dirk

PY - 2002/11/1

Y1 - 2002/11/1

N2 - Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. The disease occurs in early life with developmental delay or arrest and several neurological symptoms, e.g., seizures and dyskinesia. Both the deficiency of high-energy phosphates in neurons and the neurotoxic action of the accumulated metabolite guanidinoacetate (GAA) are candidate mechanisms for the pathophysiology of this disease. To examine a potential role of GAA accumulation, we analyzed the electrophysiological responses of neurons induced by GAA application in primary culture and acute murine brain slices. GAA evoked picrotoxin- and bicuculline-sensitive GABA(A) receptor-mediated chloride currents with an EC(50) of 167 microM in cortical neurons. Pathophysiologically relevant GAA concentrations hyperpolarized globus pallidus neurons and reduced their spontaneous spike frequency with an EC(50) of 15.1 microM. Furthermore, GAA acted as a partial agonist at heterologously expressed GABA(A) but not GABA(B) receptors. The interaction of GAA with neuronal GABA(A) receptors represents a candidate mechanism explaining neurological dysfunction in GAMT deficiency.

AB - Guanidinoacetate methyltransferase (GAMT) deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. The disease occurs in early life with developmental delay or arrest and several neurological symptoms, e.g., seizures and dyskinesia. Both the deficiency of high-energy phosphates in neurons and the neurotoxic action of the accumulated metabolite guanidinoacetate (GAA) are candidate mechanisms for the pathophysiology of this disease. To examine a potential role of GAA accumulation, we analyzed the electrophysiological responses of neurons induced by GAA application in primary culture and acute murine brain slices. GAA evoked picrotoxin- and bicuculline-sensitive GABA(A) receptor-mediated chloride currents with an EC(50) of 167 microM in cortical neurons. Pathophysiologically relevant GAA concentrations hyperpolarized globus pallidus neurons and reduced their spontaneous spike frequency with an EC(50) of 15.1 microM. Furthermore, GAA acted as a partial agonist at heterologously expressed GABA(A) but not GABA(B) receptors. The interaction of GAA with neuronal GABA(A) receptors represents a candidate mechanism explaining neurological dysfunction in GAMT deficiency.

KW - Animals

KW - Animals, Newborn

KW - Bicyclo Compounds, Heterocyclic

KW - Binding Sites

KW - Brain

KW - Brain Diseases, Metabolic, Inborn

KW - CHO Cells

KW - Chloride Channels

KW - Creatine

KW - Cricetinae

KW - Female

KW - GABA Antagonists

KW - GABA-A Receptor Agonists

KW - GABA-A Receptor Antagonists

KW - GABA-B Receptor Agonists

KW - GABA-B Receptor Antagonists

KW - Globus Pallidus

KW - Glycine

KW - Guanidinoacetate N-Methyltransferase

KW - Membrane Potentials

KW - Methyltransferases

KW - Mice

KW - Mice, Inbred C57BL

KW - Neurons

KW - Oocytes

KW - Receptors, GABA-A

KW - Receptors, GABA-B

KW - Recombinant Fusion Proteins

KW - Sulfur Radioisotopes

KW - Xenopus

M3 - SCORING: Journal article

C2 - 12505422

VL - 11

SP - 298

EP - 307

JO - NEUROBIOL DIS

JF - NEUROBIOL DIS

SN - 0969-9961

IS - 2

ER -