Differential effects of linear and cyclic polyamines on NMDA receptor activities.
The linear polyamine spermine enhances N-methyl-d-aspartate (NMDA) receptors activity at depolarized membrane potential and shows a voltage-dependent block. Spermine potentiates NMDA receptor currents in the presence of saturating concentrations of glutamate and glycine, but cyclic polyamines such as CP2323 do not. CP2323 inhibited the currents most potently amongst 10 kinds of cyclic polyamines tested. The inhibition was prominent at heteromeric NR1/NR2A and NR1/NR2B receptors but not at NR1/NR2C and NR1/NR2D receptors expressed in Xenopus oocytes. Inhibition by CP2323 was voltage-dependent, because the degree of inhibition was in the order -100mV>-70mV>-20mV. It was 10-100 times more prominent than inhibition by spermine. The inhibitory potency of both CP2323 and spermine was attenuated by the mutations around the vestibule of the channel pore at NR1 W563, N650, T807, and NR2B Y646. Inhibition by CP2323 was hardly affected by the mutations of NR1 N616 and E621, whereas inhibition by spermine was reduced by these mutations. The results suggest that CP2323 interacts with the vestibule region of the NMDA receptor and does not enter deep into the channel. Mutations of NR2B W607 greatly reduced the inhibition by CP2323 and spermine, suggesting that the mutation of this residue may cause the change of the channel structure. Neuroprotective effects of cyclic polyamines against cell damage caused by NMDA were compared with those of spermine in cultured rat hippocampal neurons. Addition of CP2323, but not spermine, into the medium attenuated the neurotoxicity induced by NMDA. These results indicate that CP2323 functions as a channel blocker of the NMDA receptor.
Masuko
Takashi
T
College of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba 274-8555, Japan.
Miyake
Muneharu
M
Kusama-Eguchi
Kuniko
K
Koike
Tohru
T
Kimura
Eiichi
E
Kizawa
Yasuo
Y
Kashiwagi
Keiko
K
Igarashi
Kazuei
K
Kusama
Tadashi
T
D000818:Animals; D002478:Cells, Cultured; D003001:Cloning, Molecular / Q000187:drug effects; D018846:Excitatory Amino Acids / Q000633:toxicity; D005260:Female; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D008968:Molecular Conformation; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011073:Polyamines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013096:Spermine / Q000494:pharmacology; D014982:Xenopus laevis
D018846:Excitatory Amino Acids; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D018696:Neuroprotective Agents; D011073:Polyamines; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; D005998:Glycine