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.
authors.affiliation: Zentrum für Molekulare Neurobiologie Hamburg, Universität Hamburg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Neu
authors.forename: Henrike
authors.initials: H
authors.lastname: Neuhoff
authors.forename: Gerhard
authors.initials: G
authors.lastname: Trube
authors.forename: Susanne
authors.initials: S
authors.lastname: Fehr
authors.forename: Kurt
authors.initials: K
authors.lastname: Ullrich
authors.forename: Jochen
authors.initials: J
authors.lastname: Roeper
authors.forename: Dirk
authors.initials: D
authors.lastname: Isbrandt
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D020739:Brain Diseases, Metabolic, Inborn / Q000378:metabolism* / Q000503:physiopathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D016466:CHO Cells; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D003401:Creatine / Q000096:biosynthesis / Q000172:deficiency*; D006224:Cricetinae; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D050937:Guanidinoacetate N-Methyltransferase; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008780:Methyltransferases / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009865:Oocytes; D011963:Receptors, GABA-A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000378:metabolism; D013462:Sulfur Radioisotopes; D014981:Xenopus
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D058786:GABA-B Receptor Agonists; D058788:GABA-B Receptor Antagonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D011993:Recombinant Fusion Proteins; D013462:Sulfur Radioisotopes; C037476:tert-butylbicyclophosphorothionate; D008780:Methyltransferases; C494507:Gamt protein, mouse; D050937:Guanidinoacetate N-Methyltransferase; C004946:glycocyamine; D003401:Creatine; D005998:Glycine