Brain extracts containing a Huntington disease antigen inhibit [3H]kainate binding and block synaptosomal amino acid transport.
Fractions isolated from mammalian brain which had previously been shown to inhibit the rate of migration of peripheral blood leukocytes taken from Huntington disease cases, and also to inhibit [3H]kainic acid binding, were characterized further. By use of repeated ultrafiltration onto a 1000D MW cutoff filter, and by the isolation and extensive washing of an enriched ammonium sulfate fraction, their activity was shown not to be due to the presence of endogenous glutamate, and to be relatively selective for brain glutamate receptor binding sites. Inhibitory activity at [3H]GABA, 5-[3H]hydroxytryptamine 5HT1 and dopamine D1 or D2 binding sites was much weaker or absent. Factor extracts were also shown to act as non-competitive inhibitors of synaptosomal amino acid transport: increasing concentrations of the factor had no significant effect on the KM for the uptake of either [3H]glutamate or [3H]GABA, but at a final concentration of 66 micrograms protein x ml-1 had reduced the VMAX for [3H]glutamate uptake to approximately 20% of control, and the VMAX for [3H]GABA uptake to approximately 40% of control. This may enhance the factor's potential excitotoxicity.
Leong
D K
DK
Department of Pharmacology, University of Sydney, NSW, Australia.
Dodd
P R
PR
Johnston
G A
GA
D000596:Amino Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000032:analysis; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D006816:Huntington Disease / Q000276:immunology; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013574:Synaptosomes / Q000378:metabolism*; D014020:Tissue Extracts / Q000737:chemistry* / Q000494:pharmacology*; D014316:Tritium
D000596:Amino Acids; D000941:Antigens; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D014020:Tissue Extracts; D014316:Tritium; D018698:Glutamic Acid; D007608:Kainic Acid