AMPA-Type Glutamate Receptors — Nonselective Cation Channels Mediating Fast Excitatory Transmission in the CNS

Abstract

In recent years, considerable progress in our understanding of the molecular events underlying excitatory synaptic transmission has been made. This progress was mainly achieved by technical advances, among them the patch-clamp technique in brain slices (Edwards et al., 1989), fast application of agonists (Franke et al., 1987), and cloning and functional expression of GluR channels of the nonNMDA type (e.g., Hollmann et al., 1989). A suitable model for studying excitatory postsynaptic currents (EPSCs) in the brain slice with patch-clamp techniques is the mossy fiber synapse on CA3 pyramidal cells of rat hippocampus (MF-CA3 synapse). This synapse is located close to the cell soma and should provide almost ideal space-clamp conditions. A comparison of MF-CA3 EPSCs with the currents activated by fast application of glutamate on membrane patches isolated from CA3 cell somata suggests that the concentration of glutamate in the synaptic cleft during excitatory synaptic transmission is high (about 1 mM) and that the transmitter remains in the synaptic cleft only briefly (about 1 ms). It seems likely that desensitization influences the peak amplitude of the EPSC in several ways. Brief pulses of glutamate cause desensitization, from which the glutamate receptor channels recover only slowly, and micromolar ambient glutamate concentrations produce desensitization at equilibrium. From the functional properties of recombinant GluR channels, in situ hybridization data, and patch-clamp experiments on different neuronal and nonneuronal cell types, a picture of the molecular identity of native channels emerges. In neurons of the hippocampus the pharmacological features of these channels were similar to recombinant channels assembled from subunits of the AMPA/kainate subtype which are strongly expressed in these cells. The native channels are characterized by outward rectification of the steady-state I-V and low Ca permeability, similar to recombinant channels containing the GluR-B subunit. This is consistent with the ubiquitous expression of this subunit in hippocampal neurones. In contrast, GluR channels from cerebellar glial cells, which uniquely in the central nervous system lack the expression of GluR-B subunits, show double rectification and high Ca permeability. The results suggest that the native functional nonNMDA glutamate receptor channels in the CNS are assembled form subunits of the AMPA/kainate subtype in a cell-specific way, with the functional properties of GluR channels in neurones being dominated by the GluR-B subunit.