The activation-inactivation properties of membrane currents induced by the rapid application of glutamate or kainate were studied in cultured hippocampal neurons and in HEK cells transfected with a cDNA encoding the GluR6 subunit. The onset of desensitization was rapid and similar in native and recombinant channels (approximately 80 s(-1) of onset rate constant). Recovery from desensitization was slow and agonist-dependent in neurons, proceeding slightly faster in GluR6 receptors. Half-maximal activation (EC50) of native channels was obtained at a glutamate concentration of 330 microM, while the half-maximal steady state desensitization (IC1/2) was attained at 2.8 microM. These values differed from those obtained in recombinant receptors (EC50 = 762 microM and IC1/2 = 0.44 microM). A small window under the crossing point of activation and inactivation curves was observed, indicating that, for some concentrations of either agonist, steady state channel activity could exist. In native receptors, this window presented maximum values at approximately 100 microM for glutamate, which predicted well the potency of glutamate to reduce the GABAergic drive in hippocampal slices. These data indicate that for neuronal kainate receptors, the concentrations for half activation and half inactivation differ by two orders of magnitude such that the maximum response to a maintained concentration of glutamate is small, and the steady state dose response curve is skewed and bell shaped.