Polyamine effects on the NMDA receptor in human brain.
Polyamines are thought to modulate the activation of NMDA receptors through a unique allosteric regulatory site. The effects of polyamines on the binding of [3H]MK-801 were measured in cortical and hippocampal tissue surgically removed from patients with temporal lobe epilepsy (TLE). The polyamine agonist spermidine increased the binding of [3H]MK-801 in the cortex in a dose-dependent manner and this effect could be blocked by the weak partial agonist diethylenetriamine (DET). Spermidine decreased the Kd of [3H]MK-801 for the NMDA receptor but did not alter the density of receptors. Spermidine had essentially the same effect on Kd and Bmax measured in the dentate gyrus of TLE subjects and the cortex and dentate gyrus of postmortem controls. Moreover, there was no difference in the density of binding sites between postmortem and TLE subjects in either region. The binding of [3H]MK-801 in human cortex was decreased by 30% by incubation with DET or by prewashing the tissue sections. In contrast, DET did not alter the binding of [3H]MK-801 in rat cortex and prewashing sections produced an increase rather than a decrease in binding. These results suggest that there are different endogenous modulators for the polyamine site in rat and human tissue. The inverse agonist 1,10-diaminodecane decreased the binding of [3H]MK-801 in a dose-dependent manner. These results suggest that the fundamental modulatory properties of polyamines in rat and human tissues are essentially the same and that endogenous polyamines may regulate human NMDA receptors.
Subramaniam
S
S
Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia 19104-6084.
O'Connor
M J
MJ
Masukawa
L M
LM
McGonigle
P
P
D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002102:Cadaver; D002540:Cerebral Cortex / Q000378:metabolism; D003959:Diamines / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D013095:Spermidine / Q000494:pharmacology
C065351:1,10-diaminodecane; D003959:Diamines; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; C005391:diethylenetriamine; D016291:Dizocilpine Maleate; D013095:Spermidine