17 research outputs found
Identification of the Amino Acid Subsets Accounting for the Ligand Binding Specificity of a Glutamate Receptor
AbstractIn a situation so far unique among neurotransmitter receptors, glutamate receptors share amino acid sequence similarities with the bacterial periplasmic binding proteins (PBPs). On the basis of the primary structure similarity of two bacterial periplasmic proteins (lysine/arginine/ornithine- and phosphate-binding proteins) with the chick cerebellar kainate-binding protein (KBP), a member of the ionotropic glutamate receptor family, we have generated a three-dimensional model structure of the KBP extracellular domain. By an interplay between homology modeling and site-directed mutagenesis, we have investigated the kainate binding properties of 55 different mutants (corresponding to 43 positions) and studied the interactions of some of these mutants with various glutamatergic ligands. As a result, we present here the subsets of amino acids accounting for the binding free energies and specificities of KBP for kainate, glutamate, and CNQX and propose a three-dimensional model, at the microarchitectural level, of the glutamatergic binding domain
Autoimmune Epilepsy: Some Epilepsy Patients Harbor Autoantibodies to Glutamate Receptors and dsDNA on both Sides of the Blood-brain Barrier, which may Kill Neurons and Decrease in Brain Fluids after Hemispherotomy
Purpose: Elucidating the potential contribution of specific autoantibodies (Ab's)
to the etiology and/or pathology of some human epilepsies. Methods: Six epilepsy
patients with Rasmussen's encephalitis (RE) and 71 patients with other epilepsies
were tested for Ab's to the âBâ peptide (amino acids 372-395) of the glutamate/AMPA
subtype 3 receptor (GluR3B peptide), double-stranded DNA (dsDNA), and
additional autoimmune disease-associated autoantigens, and for the ability of their
serum and cerebrospinal-fluid (CSF) to kill neurons. Results: Elevated anti-GluR3B
Ab's were found in serum and CSF of most RE patients, and in serum of 17/71
(24%) patients with other epilepsies. In two RE patients, anti-GluR3B Ab's
decreased drastically in CSF following functional-hemispherotomy, in association
with seizure cessation and neurological improvement. Serum and CSF of two RE
patients, and serum of 12/71 (17%) patients with other epilepsies, contained
elevated anti-dsDNA Ab's, the hallmark of systemic-lupus-erythematosus. The sera
(but not the CSF) of some RE patients contained also clinically elevated levels of
âclassicalâ autoimmune Ab's to glutamic-acid-decarboxylase,
cardiolipin,
ÎČ2-glycoprotein-I and nuclear-antigens SS-A and RNP-70. Sera and CSF of some
RE patients caused substantial death of hippocampal neurons. Conclusions: Some
epilepsy patients harbor Ab's to GluR3 and dsDNA on both sides of the blood-brain
barrier, and additional autoimmune Ab's only in serum. Since all these Ab's may
be detrimental to the nervous system and/or peripheral organs, we recommend
testing
for their presence in epilepsy, and silencing their activity in Ab-positive patients