Anxiolytic-like effects through a GLUK5 kainate receptor mechanism
Section snippets
Cell culture
All cell and tissue culture reagents were from Invitrogen (Grand Island, New York). Recombinant human AMPA receptors (GLUA1–4, both flip (i) and flop (o) variants) were stably expressed in human embryonic kidney (HEK) 293 cell lines, with the exception of GLUA3o, which was stably expressed in AV12 cells. Cells were grown as monolayers under 5% CO2 at 37 °C in Dulbecco's Modified Eagle Medium with 4.5 g/L d-glucose, l-glutamine and pyridoxine HCl (Invitrogen, Catalog #11965-084), with 10% fetal
Results
LY382884 has been shown to be a selective antagonist of the GLUK5 receptor (e.g., Bortolotto et al., 1999, Alt et al., 2004; see Table 1). We further characterized this compound at AMPA receptor subunits. LY382884 demonstrated selectivity for GLUK5 over all of the AMPA receptor subunits. The only AMPA receptor subunit for which LY382884 had any measurable affinity (>20% inhibition at 300 μM) was GLUA4i. The antagonist potency of LY382884 at GLUA4i was 25 times less than that of the AMPA
Discussion
The present findings provide the first direct evidence that selective blockade of GLUK5 receptors might be associated with anxiolysis. Although previous studies have demonstrated anxiolytic-like effects of a structurally related decahydroisoquinoline (Benvenga et al., 1995, Alt et al., 2006), LY293558 is not selective for GLUK5 receptors, exhibiting a similarly high affinity for all human cloned AMPA receptors as well (Alt et al., 2006). In contrast, LY382884 is devoid of appreciable affinity
Acknowledgements
We thank Dr. Linda Rorick-Kehn for helpful suggestions on the manuscript.
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