SELECTIVE ANTAGONISM OF NATIVE AND CLONED KAINATE AND NMDA RECEPTORS BY POLYAMINE-CONTAINING TOXINS

Antagonism of rat excitatory amino acid receptors by a synthetic analo g [philanthotoxin-343 (PhTX-343)] of a polyamine amide, wasp toxin (ph ilanthotoxin-433) and a structurally related spider toxin, argiotoxin- 636 (ArgTX-636), was examined in Xenopus oocytes injected with rat bra in RNA or RNA transcribed from the excitatory amino acid receptor clon es GluR1, GluR2 and NMDAR1. Antagonism of both kainate- and N-methyl-D -aspartate (NMDA)-elicited responses by PhTX-343 and ArgTX-636 was rev ersible, noncompetitive and partly voltage-dependent. Dose-inhibition curves were constructed using EC50 concentrations of kainate (100 muM) and N-methyl-D-asparate (33 muM) in the presence of variable concentr ations of ArgTX-636 and PHTX-343. In oocytes injected with rat brain R NA, IC50s for antagonism of kainate-induced currents were similar, i.e ., 0.07 muM and 0.12 muM for ArgTX-636 and PhTX-343, respectively, whe reas IC50S for antagonism of NMDA-induced currents were dissimilar, i. e., 0.04 muM for ArgTX-636 and 2.5 muM for PhTX-343. In oocytes expres sing NMDAR1, IC50s were similar to those for the antagonism of NMDA-in duced currents of oocytes injected with rat brain RNA. PhTX-343 and Ar gTX-636 were more or less equally potent (IC50s were 2.8 muM and 3.4 m uM, respectively) antagonists of the response of GluR1 to 100 muM kain ate. However, GluR1 was approximately 50 times less sensitive to the t oxins than non-N-methyl-D-aspartate receptors expressed in oocytes inj ected with rat brain RNA. Receptors co-expressed from GluR1 + GluR2 we re virtually insensitive to PhTX-343 (IC50 = 270 muM) and to ArgTX-343 (IC50 almost-equal-to 300 muM).