AMPA RECEPTOR-MEDIATED REGULATION OF A G(I)-PROTEIN IN CORTICAL-NEURONS

Excitatory synaptic transmission in the central nervous system is medi ated primarily by the release of glutamate from presynaptic terminals onto postsynaptic channels gated by N-methyl-D-aspartate (NMDA) and ph a-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors(1,2) . The myriad intracellular responses arising from the activation of th e NMDA and AMPA receptors have previously been attributed to the flow of Ca2+ and/or Na+ through these ion channels(1-6). Here we report tha t the binding of the agonist AMPA. to its receptor can generate intrac ellular signals that are independent of Ca2+ and Na+ in rat cortical n eurons, In the absence of intracellular Ca2+ and Na+, AMPA, but not NM DA, brought about changes in a guanine-nucleotide-binding protein (G a lpha(il)) that inhibited pertussis toxin-mediated ADP-ribosylation of the protein in an in vitro assay, This effect was observed in intact n eurons treated with AMPA as well as in isolated membranes exposed to A MPA, and was also found in MIN6 cells, which express functional AMPA r eceptors but have no metabotropic glutamate receptors, AMPA also inhib ited forskolin-stimulated activity of adenylate cyclase in neurons, de monstrating that G(i) proteins were activated. Moreover, both G beta g amma blockage and co-precipitation experiments demonstrated that the m odulation of the G(i) protein arose from the association of G alpha(il ) with the glutamate receptor-1 (GluR1) subunit, These results suggest that, as well as acting as an ion channel, the APA receptor can exhib it metabotropic activity.