beta-Amyloid (25-35) or substance P stimulates [3H]MK-801 binding to rat cortical membranes in the presence of glutamate and glycine.
Micromolar concentrations of beta-amyloid (25-35) or substance P stimulated [3H]MK-801 binding in the presence of low concentrations of glutamate (1 microM) and glycine (0.02 microM). Unlike polyamines spermine and spermidine, neither beta-amyloid (25-35) nor substance P increased [3H]MK-801 binding in the presence of maximally stimulating concentrations of glutamate and glycine. 5,7-Dichloro-kynurenic acid, CGS-19755, and arcaine completely inhibited the stimulated [3H]MK-801 binding. There was an apparent decreased potency of the [3H]MK-801 binding inhibition curve for 5,7-dichlorokynurenic acid, but not CGS-19755 or arcaine, in the presence of either beta-amyloid (25-35) or substance P. The compounds do not appear to act through the strychnine-insensitive glycine binding site because neither beta-amyloid (25-35) nor substance P displaced [3H]glycine binding. Full-length beta-amyloid (1-40), up to 10 microM, did not stimulate [3H]MK-801 binding. Concentrations > 10 microM could not be tested because they formed large aggregate precipitates in the assay. The data indicate that beta-amyloid (25-35) or substance P does not stimulate [3H]MK-801 binding at either the N-methyl-D-aspartate, glycine, or polyamine binding sites. Furthermore, the nonpeptide substance P receptor (NK1) antagonist, CP-96,345, did not block beta-amyloid (25-35)- or substance P-stimulated [3H]MK-801 binding. Therefore, the effect is not due to an interaction between the substance P receptors and the N-methyl-D-aspartate receptor-operated ionophore. Finally, if these observations can be verified using single-channel recording techniques, they may have implications in the pattern of selective neuronal loss observed in patients with neurodegenerative processes such as Alzheimer's, Parkinson's, and Huntington's diseases.
Calligaro
D O
DO
Department of Biochemical Toxicology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
O'Malley
P J
PJ
Monn
J A
JA
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism*; D016291:Dizocilpine Maleate / Q000378:metabolism*; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D005998:Glycine / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008969:Molecular Sequence Data; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D010446:Peptide Fragments / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013373:Substance P / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D001645:Biguanides; D005971:Glutamates; D010446:Peptide Fragments; D010875:Pipecolic Acids; D016194:Receptors, N-Methyl-D-Aspartate; C074636:amyloid beta-protein (25-35); D013373:Substance P; D018698:Glutamic Acid; C053672:selfotel; C006624:arcaine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D005998:Glycine