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 ɛ subunits (ɛ1-ɛ4) 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 ɛ/ζ heteromeric NMDA receptor channels expressed in Xenopus laevis oocytes were examined using the two-electrode voltage clamp method. Agmatine inhibited the four ɛ/ζ (ɛ1/ζ1, ɛ2/ζ1, ɛ3/ζ1 and ɛ4/ζ1) channels with similar sensitivity (an IC50 value of about 300 μM at −70 mV). This effect was dependent on the membrane potential and was more pronounced at hyperpolarized membrane potentials (voltage-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.