Effects of beta-amyloid-(25-35) peptides on radioligand binding to excitatory amino acid receptors and voltage-dependent calcium channels: evidence for a selective affinity for the glutamate and glycine recognition sites of the NMDA receptor.
The neurotoxic fragment corresponding to residues 25-35 of the beta-amyloid (A beta) peptide [A beta-(25-35)] has been shown to exert effects on (+)-[3H]5-methyl-10, 11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine maleate ([3H]MK-801) binding to the cation channel of the N-methyl-D-aspartate (NMDA) receptor. In the present study, we investigated whether the amidated and carboxylic acid C-terminated forms of A beta-(25-35) [A beta-(25-35-NH2) and A beta-(25-35-COOH), respectively] exert effects on other excitatory amino acid receptor and cation channel types in rat cortical membranes. Both A beta-(25-35-NH2) and A beta-(25-35-COOH) gave statistically significant dose-dependent inhibitions of [3H]glutamate and [3H]glycine binding to the agonist recognition sites of the NMDA receptor. Ten microM A beta-(25-35-NH2) and A beta-(25-35-COOH) gave 25% and 20% inhibitions of [3H]glutamate binding and 75% and 70% inhibitions of [3H]glycine binding, respectively. A beta-(25-35-NH2), but not A beta-(25-35-COOH), gave a small (ca. 17% at 10 microM) statistically significant increase of [3H]amino-3-hydroxy-5-methylisoxazole-4-propionate ([3H]AMPA) binding. [3H]kainate binding was not significantly affected by either peptide. Similarly, neither peptide affected either the maximal level or EC50 value for calcium stimulation of [3H]nitrendipine binding. It is concluded that A beta-(25-35) shows slight affinity for the agonist recognition sites of the NMDA receptor, but not for other excitatory amino acid receptor types or for L-type voltage-dependent calcium channels.
Cowburn
R F
RF
Karolinska Institute, Department of Clinical Neuroscience and Family Medicine, Huddinge, Sweden. richard.cowburn@kfcm13.hs.sll.se
Wiehager
B
B
Trief
E
E
Li-Li
M
M
Sundström
E
E
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017470:Receptors, Glutamate / Q000187:drug effects* / Q000378:metabolism; D018009:Receptors, Glycine / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000378:metabolism
D016229:Amyloid beta-Peptides; D015220:Calcium Channels; D010446:Peptide Fragments; D017470:Receptors, Glutamate; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; C074636:amyloid beta-protein (25-35); D018698:Glutamic Acid