title: The contributions of GluR2 to allosteric modulation of AMPA receptors.
abstract: Native AMPA receptor complexes in the CNS are composed of hetero-oligomers of the GluR1-4 subunits, and generally contain the GluR2 subunit. To determine the contributions of GluR2 to pharmacological properties of receptor complexes, the effect of hetero-oligomerization with GluR2 on allosteric modulation of recombinant AMPA receptors was studied. The study of homo-oligomeric GluR2 was facilitated with a site-directed mutant of the pore, GluR2(R607Q), which allowed robust currents from this normally low-conducting subunit. The efficacy of the allosteric modulators was tested on homo-oligomeric GluR1-4, and then compared with hetero-oligomeric GluR1/GluR2, GluR3/GluR2 and GluR4/GluR2. Two selective allosteric modulators were tested, a positive modulator, cyclothiazide, and a negative modulator, LY300164. The results show that the pharmacological properties of homo-oligomeric GluR2 are not significantly different from those of GluR1, GluR3 or GluR4. The apparent affinity of cyclothiazide is not significantly changed upon hetero-oligomerization. However, the extent of potentiation of kainate responses by cyclothiazide is significantly decreased upon hetero-oligomerization. Hetero-oligomerization increases the apparent affinity of LY300164, a (-) isomer of the 2,3-benzodiazepine LY293606. These data indicate that although GluR2 has a dominant effect on the permeation properties, this subunit does not have a similarly dominant effect on pharmacological properties of native receptors. However, the state of hetero-oligomerization can alter the pharmacological properties of AMPA receptors.
authors.affiliation: Department of Anatomy and Neurobiology, Colorado State University, Fort Collins 80523-1670, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Cotton
authors.forename: K M
authors.initials: KM
authors.lastname: Partin
mesh_terms: D000494:Allosteric Regulation; D019943:Amino Acid Substitution; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology; D001581:Benzothiadiazines / Q000737:chemistry / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis
chemical_list: D001569:Benzodiazepines; D001581:Benzothiadiazines; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D011994:Recombinant Proteins; C104723:glutamate receptor ionotropic, AMPA 3; C104724:glutamate receptor ionotropic, AMPA 4; C079692:GYKI 53655; C085266:talampanel; C104722:glutamate receptor ionotropic, AMPA 2; C004639:cyclothiazide