Abstract
We investigated in rat hippocampus neurons whether 4-(aminobutyl)guanidine (agmatine), formed by decarboxylation ofl-arginine by arginine decarboxylase and metabolized to urea and putrescine, can modulate the function ofN-methyl-d-aspartate (NMDA) receptor channels. In cultured hippocampal neurons studied by whole-cell patch clamp, extracellular-applied agmatine produced a voltage- and concentration-dependent block of NMDA but not α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid nor kainate currents. Analysis of the voltage dependence of the block suggests that agmatine binds at a site located within the NMDA channel pore with a dissociation constant of 952 μM at 0 mV and an electric distance of 0.62. We also tested effects of several agmatine analogs. Arcaine (1,4-butyldiguanidine) also produced a similar voltage-dependent block of the NMDA current, whereas putrescine (1,4-butyldiamine) had little effect, suggesting that the guanidine group of agmatine is the active moiety when blocking the NMDA channel. Moreover, spermine (an endogenous polyamine) potentiated the NMDA current even in the presence of blocker agmatine or arcaine, suggesting that the guanidine-containing compounds agmatine and arcaine interact with the NMDA channel at a binding site different from that of spermine. Our results indicate that in hippocampal neurons agmatine selectively modulates the NMDA subclass of glutamate receptor channels mediated by the interaction between the guanidine group and the channel pore. The results support other data that agmatine may function as an endogenous neurotransmitter/neuromodulator in brain.
Footnotes
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Send reprint requests to: Xian-Cheng Yang, Division of Neurobiology, Cornell University Medical College, 411 East 69th St., KB410, New York, NY 10021. E-mail: xcyang{at}mail.med.cornell.edu
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↵1 The work was supported by National Institutes of Health Grant NHLBI-HL 18974.
- Abbreviations:
- NMDA
- N-methyl-d-aspartate
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
- ADC
- arginine decarboxylase
- AP5
- (±)-2-amino-5-phosphonopentanoic acid
- Received April 30, 1998.
- Accepted September 8, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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