The agonist selectivity of a class III metabotropic glutamate receptor, human mGluR4a, is determined by the N-terminal extracellular domain

M. A. Tones, N. Bendali, P. J. Flor, T. Knopfel*, R. Kuhn

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

45 Citations (Scopus)

Abstract

To test the hypothesis that the determinants for agonist selectivity of class III metabotropic glutamate receptors (mGluRs) are localized in the N-terminal extracellular domain, a chimaeric cDNA was constructed where 519 amino acids of the N-terminal extracellular domain of human mGluRlb were exchanged with the corresponding region of human mGIuR4. The pharmacological profile of the chimaera, designated hmGluR41-519/1b, was analysed by recordings of intracellular calcium concentration ([Ca2+]i) in transiently transfected HEK 293 cells and compared with that of human mGluR4b and human mGluR4a stably expressed in Chinese hamster ovary cells. Application of l00μM L-2-amino-4-phosphonobu-tyrate (L-AP4), a class HI mGluR-specific agonist, induced a rise in [Ca2+]i in hmGluR41-519/1b but not in hmGluRlb expressing cells. In contrast, application of quisqualate (100/μM) induced a rise in [Ca2+]i at hmGluR1b but not at hmGluR41-519/1b. Dose-response analysis with L-AP4 and L-glutamate at hmGluR41-519/1b revealed a half-maximal effect (EC50) of 16.0/μM and 196μM, respectively. The EC50 values for quisqualate, glutamate and (1S,3R)-ACPD at hmGluRlb were 10.25 /μM, 225 fiM and 3060/μM, respectively. The rank order of agonist potency of hmGluR41-519/1b corresponds to that of hmGluR4 (L-AP4 > L-glutamate > (1S,3R)-ACPD > quisqualate) but is different from that of hmGluRlb (quisqualate > glutamate > (1S,3R)-ACPD).

Original languageEnglish
Pages (from-to)117-120
Number of pages4
JournalNeuroReport
Volume7
Issue number1
DOIs
Publication statusPublished - 29 Dec 1995

User-Defined Keywords

  • Calcium
  • Chimaeric receptors
  • G-protein-coupled receptors
  • Signal transduction

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