title: Differential regulation of ionotropic glutamate receptors.
abstract: Ionotropic glutamate receptors (iGluRs), a family of ligand-gated ion channels, are responsible for the majority of fast excitatory neurotransmission in the central nervous system. Within this family, different members serve distinct roles at glutamatergic synapses. Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors mediate fast depolarization while N-methyl-D-aspartate (NMDA) receptors mediate the slower component of the excitatory postsynaptic potential. These disparate functions suggest alternate modes of regulation. In this work, we show that endogenous regulators of iGluRs have different abilities to bind to specific domains of NMDA NR1-1b and AMPA GluR2 subunits. We have previously shown that the sulfated neurosteroids pregnenolone sulfate and 3alpha-hydroxy-5beta-pregnan-20-one sulfate bind to the extracellular glutamate-binding core (S1S2) of the GluR2 subunit. Here we show that neither neurosteroid binds to the S1S2 domain of the NMDA NR1-1b subunit. This NR1-1b NMDA domain does, however, bind to the endogenous polyamines spermine and spermidine as well as Zn(II). Binding of the polyamines and Zn(II) to the S1S2 domain of the GluR2 subunit was not observed. This binding of Zn(II) and polyamines to the S1S2 domain of the NR1-1b subunit defines a new binding site for each of these modulators.
authors.affiliation: Department of Chemistry, Western Washington University, Bellingham, Washington, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Stoll
authors.forename: James
authors.initials: J
authors.lastname: Hall
authors.forename: Nick
authors.initials: N
authors.lastname: Van Buren
authors.forename: Amanda
authors.initials: A
authors.lastname: Hall
authors.forename: Lee
authors.initials: L
authors.lastname: Knight
authors.forename: Andy
authors.initials: A
authors.lastname: Morgan
authors.forename: Sarah
authors.initials: S
authors.lastname: Zuger
authors.forename: Halena
authors.initials: H
authors.lastname: Van Deusen
authors.forename: Lisa
authors.initials: L
authors.lastname: Gentile
mesh_terms: D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D011280:Pregnanolone / Q000737:chemistry; D011284:Pregnenolone / Q000737:chemistry; D017434:Protein Structure, Tertiary; D018091:Receptors, AMPA / Q000737:chemistry*; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry*; D013095:Spermidine / Q000737:chemistry; D013096:Spermine / Q000737:chemistry; D015032:Zinc / Q000737:chemistry
chemical_list: D008024:Ligands; C409466:NR1 NMDA receptor; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; C018370:pregnenolone sulfate; D013096:Spermine; D011284:Pregnenolone; D011280:Pregnanolone; D015032:Zinc; C104722:glutamate receptor ionotropic, AMPA 2; D013095:Spermidine