Polyamines, NMDA receptors

Histaminergic activation of ion channels may also occur through NMDA receptors [ 1 ]. This action occurs at the polyamine binding site on NR1/NR2B subunits and is sensitive to pH. Endogenous histamine may act at this site to facilitate the induction of long term potentiation, but this has not been established. Additional histamine receptors may still be discovered. 

Traynelis, S. F., Hartley M. and Heinemann, S. F. Control of proton sensitivity of the NMDA receptor by RNA splicing and polyamines. Science 268 873-876,1995. 

In addition to the glutamate and glycine sites on the NMDA receptor, there also exist polyamine sites which are activated by the naturally occurring polyamines spermine and spermidine. Specific divalent cation sites are also associated with the NMDA receptor, namely the voltage-dependent magnesium site and the inhibitory zinc site. In addition to the excitatory amino acids, the natural metabolite of brain tryptophan, quinolinic acid, can also act as an agonist of the NMDA receptor and may contribute to nerve cell death at high concentrations. 

Wiley JL, Cristello AF, Balster RL (1995) Effects of site-selective NMDA receptor antagonists in an elevated plus-maze model of anxiety in mice. Eur J Pharmacol 294 101-107 Williams K (1997) Modulation and block of ion channels a new biology of polyamines. Cell Signal 9 1-13... 

Bernardi, M., Bertolini, A., Szczawinska, K., Genedani, S. Blockade of the polyamine site of NMDA receptors produces antinociception and enhances the effect of morphine, in mice, Eur. J. Pharmacol. 1996, 298, 51-55. 

FIGURE 10—24. Five modulatory sites on the N-methyW-aspartate (NMDA) receptor. The NMDA glutamate—calcium channel complex has multiple receptors in and around it, which act in concert as allosteric modulators. Three of these modulatory sites are located around the NMDA receptor. One of these modulatory sites is for the neurotransmitter glycine, another is for polyamines, and yet another is for zinc. Two of the modulatory sites are located inside or near the ion channel itself. The magnesium ion can block the calcium channel at one of these modulatory site, which is presumably inside the ion channel or close to it. The other inhibitory modulatory site, located inside the ion channel, is sometimes called the PCP site, since the psychotomimic agent phencylclidine (PCP) binds to this site. 

A polyamine-binding site is in the NMDA receptor complex (Singh et al., 1990 Ransom and Stec, 1988). Like the glycine-binding site, the polyamine modulatory... 

Singh L., Oles R., and Woodruff G. (1990). In vivo interaction of a polyamine with the NMDA receptor. Eur. J. Pharmacol. 180 391-392. 

Initially, ifenprodil was reported to bind to the polyamine site of NMDA receptors, but recent studies indicate that it acts on a site distinct from the polyamine site (Gallagher et al., 1996 Yamakura and Shimoji, 1999). Arginine-337 in the NR2B subunit is absolutely required for high affinity ifenprodil inhibition, but not for... 

Figure 14.8. Sites of action of endogenous ligands and drugs that modulate the action of excitatory amino acids on the NMDA receptor. Recent evidence shows that glutamate (Glut) and possibly other excitatory amino acids released from presynaptic terminals activate the NMDA receptor site on postsynaptic membranes, resulting in the opening of the Na+/Ca++ channels. Glycine acts on a strychnine-insensitive receptor while polyamines (e.g. spermine and spermidine) also have a modulatory role. Conversely Zn++ and Mg++ and drugs like phencyclidine (PCP) block the ion channel by acting at various sites on the NMDA receptor complex or...

FIGURE 4 Metabolic pathway of polyamines. Increased levels of spermidine, spermine, putrescine, acetylspermidine, and acetylspermine without a change of ornithine in AD pathology were observed. One theory suggests that the NMDA receptor excitotoxicity is caused by an excess of spermidine and spermine due to ornithine decarboxylase activity induced by plaque and/or tangle deposition in specific brain regions. Reproduced from Ref. (112). 

The NMDA receptor ion-channel complex has been demonstrated to play an important role in spinal nociceptive transmission (Dickenson et al., 1997 Zhang et al., 2002). In addition to possessing the NMDA receptor, to which glutamate binds, the NMDA receptor ion-channel complex contains several allosteric sites such as polyamine and glycine recognition sites that modulate the receptor function (for a review, see Williams et al., 1991). Our behavioral studies indicate that both spinal polyamine and glycine recognition sites of the NMDA receptor ion-channel complex play the crucial role in nociceptive transmission (Tan-No et al., 2000, 2007). 

In summary, evidence is presented that i.t.-administered big dynorphin at extremely low doses produces nociceptive behavior. This effect seems to be mediated through the activation of the NMDA receptor ion-channel complex by acting on the polyamine recognition site because the peptide has a strong positive charge. 

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