Activation of GABAA Receptors by Guanidinoacetate: A Novel Pathophysiological Mechanism

@article{Neu2002ActivationOG,
  title={Activation of GABAA Receptors by Guanidinoacetate: A Novel Pathophysiological Mechanism},
  author={Axel Neu and Henrike Neuhoff and Gerhard Trube and Susanne Fehr and Kurt Ullrich and Jochen Roeper and Dirk Isbrandt},
  journal={Neurobiology of Disease},
  year={2002},
  volume={11},
  pages={298-307}
}
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… 
View on Elsevier
pdf.enp.org
118 Citations
Highly Influential Citations
7
Background Citations
63

Figures from this paper

118 Citations

Guanidinoacetate (GAA) is a potent GABAA receptor GABA mimetic: Implications for neurological disease pathology

It is concluded that orthosteric activation of GABAARs by GAA, and potentially other GABAAR mimetic guanidino compounds (GCs) like γ‐GBA and GES, interferes with normal inhibitory GABAergic neurotransmission which could mediate, and contribute to, neurotoxicity.

Activation of cerebellar granule cells GABAA receptors by guanidinoacetate

Guanidinoacetate methyltransferase deficiency

The discussion of this review focuses on various and latest studies addressing GAMT deficiency and creatine metabolism, as well as addresses the question of neurotoxicity GAA.

Intrastriatal Administration of Guanidinoacetate Inhibits Na+, K+-ATPase and Creatine Kinase Activities in Rat Striatum

The results suggest that the inhibition of these enzymes by increased intracerebral levels of GAA may contribute to the neuropathology observed in patients with GAMT-deficiency.

Guanidino Acids Act as ρ1 GABAC Receptor Antagonists

The results of this study contribute to the structure–activity-relationship profile required in developing novel therapeutic agents for GABAC receptors by indicating that steric effects may impact on activity.

Evaluation of the mechanism underlying the inhibitory effect of guanidinoacetate on brain Na+, K+-ATPase activity

2-Guanidine-4-methylquinazoline acts as a novel competitive antagonist of A type γ-aminobutyric acid receptors

Astrocytic γ-aminobutyric acid (GABA) transporters mediate guanidinoacetate transport in rat brain

Gene therapy for guanidinoacetate methyltransferase deficiency restores cerebral and myocardial creatine while resolving behavioral abnormalities

Ammonia toxicity to the brain

Several potential neuroprotective strategies have been put forward recently, including the use of NMDA receptor antagonists, nitric oxide inhibitors, creatine, acetyl-L-carnitine, CNTF or inhibitors of MAPKs and glutamine synthetase.
...

27 References

Uraemic guanidino compounds inhibit γ-aminobutyric acid-evoked whole cell currents in mouse spinal cord neurones

Guanidino compounds that are increased in hyperargininemia inhibit GABA and glycine responses on mouse neurons in cell culture

Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism.

Cerebellar GABAA receptor selective for a behavioural alcohol antagonist

It is concluded that this α-subunit is part of a cerebellar receptor subtype, selective for Rol5-4513 (refs 17, 18), an antagonist of alcohol-induced motor incoordination and ataxia, and photoaffinity-labelled with benzodiazepines.

Guanidino compounds in guanidinoacetate methyltransferase deficiency, a new inborn error of creatine synthesis.

Functional characteristics and sites of gene expression of the alpha 1, beta 1, gamma 2-isoform of the rat GABAA receptor

Cl cloning of the gamma 2-subunit cDNA of rat brain and its functional analysis by coexpression with the alpha 1- and beta 1-subunits in Xenopus oocytes, and on the sites of gene expression of the 3 subunits in the rat brain suggest that thealpha 1, beta 1, and gamma 1- subunits are likely receptor constituents in some neuronal populations.

Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation.

Dietary treatment with arginine restriction in combination with ornithine supplementation represents a new and rationale therapeutic approach in GAMT deficiency and indicates for the first time that GAA may exert an important epileptogenic potential in man.

Convulsive action and toxicity of uremic guanidino compounds: behavioral assessment and relation to brain concentration in adult mice

Creatine replacement therapy in guanidineoacetate methyltransferase deficiency, a novel inborn error of metabolism

Calcium sensing properties of the GABAB receptor