Multiple-conductance channels activated by excitatory amino acids in cerebellar neurons

Abstract

In the mammalian central nervous system amino acids such as L-glutamate and L-aspartate are thought to act as fast synaptic transmitters. It has been suggested that at least three pharmacologically-distinguishable types of glutamate receptor occur in central neurons and that these are selectively activated by the glutamate analogues N-methyl-D-aspartate (NMDA), quisqualate and kainate. These three receptor types would be expected to open ion channels with different conductances. Hence if agonists produce similar channel conductances this would suggest they are acting on the same receptor. Another possibility is suggested by experiments on spinal neurons, where GABA (gamma-amino butyric acid) and glycine appear to open different sub-conductance levels of one class of channel while acting on different receptors. By analogy, several types of glutamate receptor could also be linked to a single type of channel with several sub-conductance states. We have examined these possibilities in cerebellar neurons by analysing the single-channel currents activated by L-glutamate, L-aspartate, NMDA, quisqualate and kainate in excised membrane patches. All of these agonists are capable of opening channels with at least five different conductance levels, the largest being about 45-50 pS. NMDA predominantly activated conductance levels above 30 pS while quisqualate and kainate mainly activated ones below 20 pS. The presence of clear transitions between levels favours the idea that the five main levels are all sub-states of the same type of channel.

Ion channel properties of a protein complex with characteristics of a glutamate/N‐methyl‐d‐aspartate receptor

“…The 47 and 23 pS conductance levels are similar to those for NMDA-activated ion channels in neurons reported by several investigators (e.g. [23,24]). The high conductance state observed (65 pS) may be the result of chelation of free Ca 2+ and Mg 2+ by EDTA used in all steps of the isolation and reconstitution of the protein complex.…”

A family of glutamate receptor genes: Evidence for the formation of heteromultimeric receptors with distinct channel properties

“…Single-channel recordings in rat cerebellar and hippocampal neurons indicate that kainate activates channels with multiple conductances (Jahr and Stevens, 1987;Cull-Candy and Usowicz, 1987). Kainate elicits predominantly small-amplitude channel openings (less than 1 pS, 8pS, and 1S-18 pS) and large-amplitude openings of 38 pS at a much lower frequency.…”

“…Pharmacological and electrophysiological studies have defined two broad classes of glutamate receptors, which can be distinguished by their response to selective agonists. The glutamate agonist N-methyl-o-aspartate (NMDA) activates large conductance channels (Nowak et al, 1984;Jahr and Stevens, 1987;Cull-Candy and Usowicz, 1987) that are permeable to monovalent cations and calcium (MacDermott et al, 1986). A second class of glutamate-responsive channels permeable only to monovalent cations can be activated by the agonists kainate or quisqualate, but not by NMDA.…”

“…It is also possible that receptor channel complexes with multiple binding sites exist, and multiple conformational states are associated with distinct channel properties (Jahr and Stevens, 1987;Cull-Candy and Usowicz, 1987). One approach to understanding the complexity of glutamate receptors involves the cloning and characterization of the genes encoding the subunits of these receptors.…”

Biophysical model of a Hebbian synapse.

“…The associated channel is voltage-dependent due to block by Mg2`that is relieved by membrane depolarization (17)(18)(19).…”