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 epsilon subunits (epsilon1-epsilon4) 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 (epsilon1/zeta1, epsilon2/zeta1, epsilon3/zeta1 and epsilon4/zeta1) channels with similar sensitivity (an IC50 value of about 300microM at -70mV). 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.
Askalany
Ahmed R
AR
Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan.
Yamakura
Tomohiro
T
Petrenko
Andrey B
AB
Kohno
Tatsuro
T
Sakimura
Kenji
K
Baba
Hiroshi
H
D000376:Agmatine / Q000494:pharmacology*; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D004852:Epoxy Compounds / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D008845:Microinjections / Q000379:methods; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D011994:Recombinant Proteins / Q000187:drug effects; D014982:Xenopus laevis
D000447:Aldehydes; D004852:Epoxy Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D018698:Glutamic Acid; D000376:Agmatine; C007871:glycinaldehyde