Effect of agmatine on heteromeric N-methyl-D-aspartate receptor channels

Endogenous polyamines like spermine are known to have four distinct effects on recombinant N-methyl-D-aspartate (NMDA) receptor channels: voltage-dependent inhibition, glycine-dependent Stimulation, glycine-independent stimulation and decreased affinity to the agonist (L-glutamate). These effects are highly dependent on the constituting F subunits (epsilon 1-r4) of the recombinant NMDA receptor channels. Agmatine reportedly inhibits native NMDA receptor channels in cultured hippocampal neurons. In the present investigation, the effects of agmatine on the epsilon/zeta heteromeric NMDA receptor channels expressed in Xenopus laevis oocytes were examined using the two-electrode voltage clamp method. Agmatine inhibited the four epsilon/zeta (epsilon 1/zeta 1, epsilon 2/zeta 1, epsilon 4/zeta 1 and epsilon 4/zeta 1) channels with similar sensitivity (an IC50 value of about 300 mu M at -70 mV). This effect was dependent on the membrane potential and was more pronounced at hyperpolarized membrane potentials (vottage-dependent inhibition). Agmatine did not exhibit other stimulatory (glycine-dependent and -independent effects) or inhibitory (decreased affinity to L-glutamate) effects. These properties are similar to the pharmacological profile of well-characterized NMDA receptor channel blockers like phencyclidine and ketamine. Thus, regarding the effects on the NMDA receptor channels, agmatine is not like other endogenous polyamines rather it acts as a channel blocker. (c) 2005 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved.