A Molecular Determinant for Submillisecond Desensitization in Glutamate Receptors

Abstract

The decay of excitatory postsynaptic currents in central neurons mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors is likely to be shaped either by receptor desensitization or by offset after removal of glutamate from the synaptic cleft. Native AMPA receptors show desensitization time constants of 1 to about 10 milliseconds, but the underlying molecular determinants of these large differences are unknown. Cloned AMPA receptors carrying the "flop" splice variants of glutamate receptor subtype C (GluR-C) and GluR-D are shown to have desensitization time constants of around 1 millisecond, whereas those with the "flip" variants are about four times slower. Cerebellar granule cells switch their expression of GluR-D splice variants from mostly flip forms in early stages to predominantly flop forms in the adult rat brain. These findings suggest that rapid desensitization of AMPA receptors can be regulated by the expression and alternative splicing of GluR-D gene transcripts.

Excitotoxicity mediated by Ca2+-permeable GluR4-containing AMPA receptors involves the AP-1 transcription factor

“…2 Therefore, the use of CTZ allowed us to study AMPA receptor-mediated toxicity in experimental conditions more similar to those observed in several pathological conditions, such as in global ischemia and in ALS, where the molecular structure of AMPA receptors is changed, 8,9,11,23 leading to an increased Ca 2 þ permeability 7 or a slower desensitization kinetic. 24 In the presence of 100 mM CTZ, glutamate toxicity was concentration-dependent and sensitive to 50 mM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), indicating that toxicity was mediated through GluR4-homomeric AMPA receptors (Figure 1a and b). Additionally, we investigated whether excitotoxicity was dependent on the extracellular Ca 2 þ concentration in HEK-GluR4 cells.…”

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

“…Homomeric GluA4 AMPA receptors and in particular, the GluA4 'flop' splice variants show faster kinetics as compared to other types of AMPARs (Mosbacher et al, 1994;Geiger et al, 1995;Zhu, 2009), which may affect the amount of depolarization at postsynaptic neurons in response to receptor activation. The decay time of AMPA EPSCs increased during development in both WT and GluA4-/-mice (p<0.001); however, no significant differences in the kinetics of the AMPA EPSCs were detected between the genotypes at any stage of development (P4-P5: WT 4.2±0.6 ms, GluA4-/-4.6±0.4 ms; P6-P8: WT 5.6±0.7 ms, GluA4-/-5.7±0.8 ms; P14-P15: WT 10.5±0.8 ms, GluA4-/-9.6±0.8 ms; P16-P34: WT 9.3±0.9 ms, GluA4-/-10.2±0.5 ms).…”

Subunit Composition, Kinetic, and Permeation Properties of AMPA Receptors in Single Neocortical Nonpyramidal Cells

“…In heterologous expression systems recombinant AM PAR permeation properties are controlled by the relative abundance of GluR2 (for review on voltage dependence and calcium permeability, see Hollmann and Heinemann, 1994;Jonas and Burnashev, 1995) [see also Swanson et al (1997) for single channel conductance]. In contrast, their kinetic properties are affected by multiple factors, including subunit composition, flip/flop alternative splicing, and mRNA edition at the R/G site (Sommer et al, 1990;L omeli et al, 1994;Mosbacher et al, 1994;Partin et al, 1994).…”

“…In heterologous expression systems recombinant AM PAR permeation properties are controlled by the relative abundance of GluR2 (for review on voltage dependence and calcium permeability, see Hollmann and Heinemann, 1994;Jonas and Burnashev, 1995) [see also Swanson et al (1997) for single channel conductance]. In contrast, their kinetic properties are affected by multiple factors, including subunit composition, flip/flop alternative splicing, and mRNA edition at the R/G site (Sommer et al, 1990;L omeli et al, 1994;Mosbacher et al, 1994;Partin et al, 1994).Studies of native AM PARs by patch-clamp recordings combined with single-cell reverse transcription-PCR (single-cell RT-PCR; Lambolez et al, 1992) have confirmed the role played by the GluR2 subunit in their permeation (Bochet et al, 1994;Jonas et al, 1994;Geiger et al, 1995), but the identity of the molecular determinants controlling their kinetics is still controversial. Indeed, slow and fast desensitizations were correlated with either GluR2 flip and GluR4 (Geiger et al, 1995), respectively, or to flip and flop splice variants (Lambolez et al, 1996).…”