The contributions of GluR2 to allosteric modulation of AMPA receptors

Native AMPA receptor complexes in the CNS are composed of hetero-oligomers of the GluR1-4 subunits, and generally contain the GluR2 subunit. To determ ine the contributions of GluR2 to pharmacological properties of receptor co mplexes, the effect of hetero-oligomerization with GluR2 on allosteric modu lation of recombinant AMPA receptors was studied. The study of homooligomer ic GluR2 was facilitated with a site-directed mutant of the pore, GluR2(R(6 07)Q), which allowed robust currents from this normally low-conducting subu nit. The efficacy of the allosteric modulators was tested on homo-oligomeri c GluRI-4, and then compared with hetero-oligomeric GluR1/GluR2, GIuR3/GluR 2 and GluR4/GluR2. Two selective allosteric modulators were tested, a posit ive modulator, cyclothiazide, and a negative modulator, LY300164. The resul ts show that the pharmacological properties of homo-oligomeric GluR2 are no t significantly different from those of GluR 1, GluR3 or GluR4. The apparen t affinity of cyclothiazide is not significantly changed upon hetero-oligom erization. However, the extent of potentiation of kainate responses by cycl othiazide is significantly decreased upon hetero-oligomerization. Hetero-ol igomerization increases the apparent affinity of LY300164, a (-) isomer of the 2,3-benzodiazepine LY293606. These data indicate that although GluR2 ha s a dominant effect on the permeation properties, this subunit does not hav e a similarly dominant effect on pharmacological properties of native recep tors. However, the state of hetero-oligomerization can alter the pharmacolo gical properties of AMPA receptors. (C) 1999 Elsevier Science Ltd. All righ ts reserved.