Activation of GABA(A) receptors by guanidinoacetate
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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, Vol. 11, No. 2, 01.11.2002, p. 298-307.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -