Kainate Receptors Exhibit Differential Sensitivities to (S)-5-Iodowillardiine
Abstract
Characterization of the role of kainate receptors in excitatory synaptic transmission has been hampered by a lack of subtype-selective pharmacological agents. (S)-5-Iodowillardiine (IW), an analog of willardiine [(S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione], a heterocyclic amino acid found in Acacia andMimosa seeds, was previously shown to be highly potent on native kainate receptors in dorsal root ganglion neurons. We examined the responses evoked by IW from recombinant homomeric and heteromeric kainate receptors expressed in human embryonic kidney 293 cells. IW potently elicited currents from glutamate receptor 5 (GluR5)-expressing cells, but showed no activity on homomeric GluR6 or GluR7 receptors. Co-expression of these receptor subunits with KA-2 subunits produced receptors that were weakly sensitive to IW. GluR5/KA-2 receptors had a higher EC50 value than homomeric GluR5 and exhibited a much faster recovery from desensitization. Finally, we found that the IW selectivity for GluR5 compared with GluR6 was determined by amino acid 721, which was previously shown to control α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate sensitivity of these kainate receptor subunits. The pharmacological selectivity and commercial availability of IW suggests that this compound may be of use in characterizing the molecular constituents of native kainate receptor responses.
Footnotes
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Send reprint requests to: Dr. Geoffrey T. Swanson, Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037. E-mail: swanson{at}salk.edu
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This work was supported by an National Research Science Award fellowship (G.T.S.), a National Institute for Neurological Diseases and Stroke grant (S.F.H.), and a McKnight Endowment Fund for Neuroscience grant (S.F.H.).
- Abbreviations:
- AMPA
- α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate
- DRG
- dorsal root ganglion
- ATPA
- (R,S)-2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid
- IW
- (S)-5-iodowillardiine
- HEK
- human embryonic kidney
- willardiine
- (S)-1-(2-amino-2-carboxyethyl)pyrimidine-2,4-dione
- HEPES
- 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
- NMDA
- N-methyl-d-aspartate
- EGTA
- ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid
- GluR
- glutamate receptor
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- Received December 5, 1997.
- Accepted January 29, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
