Activation of GABA A Receptors by Guanidinoacetate: A Novel Pathophysiological Mechanism

• Published in: Neurobiology of disease 2002-11, Vol.11 (2), p.298-307
• Main Authors: Neu, Axel, Neuhoff, Henrike, Trube, Gerhard, Fehr, Susanne, Ullrich, Kurt, Roeper, Jochen, Isbrandt, Dirk
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Binding Sites - drug effects; Binding Sites - physiology; Brain - metabolism; Brain - physiopathology; Brain Diseases, Metabolic, Inborn - metabolism; Brain Diseases, Metabolic, Inborn - physiopathology; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Chloride Channels - drug effects; Chloride Channels - metabolism; CHO Cells; Creatine - biosynthesis; Creatine - deficiency; Cricetinae; Female; GABA Antagonists - pharmacology; GABA receptor agonist; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; GABA-B Receptor Agonists; GABA-B Receptor Antagonists; globus pallidus; Globus Pallidus - drug effects; Globus Pallidus - metabolism; Glycine - analogs & derivatives; Glycine - metabolism; Glycine - pharmacology; guanidino compounds; Guanidinoacetate N-Methyltransferase; Membrane Potentials - drug effects; Membrane Potentials - physiology; Methyltransferases - deficiency; Methyltransferases - genetics; Mice; Mice, Inbred C57BL; Neurons - drug effects; Neurons - metabolism; Oocytes; Receptors, GABA-A - metabolism; Receptors, GABA-B - metabolism; Recombinant Fusion Proteins - drug effects; Recombinant Fusion Proteins - metabolism; Sulfur Radioisotopes; Xenopus
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1006/nbdi.2002.0547

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 μM in cortical neurons. Pathophysiologically relevant GAA concentrations hyperpolarized globus pallidus neurons and reduced their spontaneous spike frequency with an EC 50 of 15.1 μM. 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.