AMPA/KA receptor binding site question

[Limpet_Chicken]

Just a quick question:

What is the function of the polyamine and neurosteroid binding sites at AMPAr and KArs?

 

[MurphyClox]

Both serve as allosteric sites for receptor regulation.

For example at the extracellular glutamate binding core of the GluR2 class of AMPA receptors bind at least two neurosteroids (pregnenolone sulfate & 3α-hydroxy-5β-pregnan-20-one sulfate), both of which negatively modulate its activity. (see: Lipids 2004, 39(8), p.811)

This is a review on that topic:

Sedlacek, M.; Korinek, M.; Petrovic, M.; Cais, O.; Adamusova, E.; Chodounska, H.; Vyklicky, L., Jr.
"Neurosteroid modulation of ionotropic glutamate receptors and excitatory synaptic transmission."
Physiological Research (Prague, Czech Republic) 2008, 57(Suppl. 3), S49-S57
General Review written in English

Abstract
A review. Ionotropic glutamate receptors function can be affected by neurosteroids, both pos. and neg. N-methyl-D-aspartate (NMDA) receptor responses to exogenously applied glutamate are potentiated or inhibited (depending on the receptor subunit component) by pregnenolone sulfate (PS) and inhibited by pregnanolone sulfate (3α,5βS).
While PS effect is most pronounced when its application precedes that of glutamate, 3α,5βS only binds to receptors already activated. Synaptically activated NMDA receptors are inhibited by 3α,5βS, though to a lesser extent than those tonically activated by exogenous glutamate. PS, on the other hand, shows virtually no effect on any of the models of synaptically activated NMDA receptors. The site of neurosteroid action at the receptor mol. has not yet been identified, however, the expts. indicate that there are at least two distinct extracellularly located binding sites for PS mediating its potentiating and inhibitory effects resp. Experiments with chimeric receptors revealed the importance of the extracellular loop connecting the third and the fourth transmembrane domain of the receptor NR2 subunit for the neurosteroid action.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors are inhibited by both PS and 3α,5βS. These neurosteroids also affect AMPA receptors-mediated synaptic transmission, however, in a rather indirect way, through presynaptically located targets of action.

I guess that the polyamine-binding-site has a modulatory function, too, but I could only find references that dealt with exogenous polyamines (like some insect toxins) as AMPA-modulators. See e.g.:
- "Design, synthesis, and pharmacological characterization of polyamine toxin derivatives: potent ligands for the pore-forming region of AMPA receptors."
ChemMedChem 2006, 1(4), p.419
- "PKC and polyamine modulation of GluR2-deficient AMPA receptors in immature neocortical pyramidal neurons of the rat."
Journal of Physiology (Oxford, United Kingdom) 2007, 581(2), p.679


PEACE! - Murphy