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The Journal of Neuroscience, January 14, 2009, 29(2):303-312; doi:10.1523/JNEUROSCI.3953-08.2009

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Cellular/Molecular
Agonist Occupancy Is Essential for Forward Trafficking of AMPA Receptors

Sarah K. Coleman,¹ Tommi Möykkynen,³ Annukka Jouppila,¹ Susanna Koskelainen,¹ Claudio Rivera,² Esa R Korpi,³ and Kari Keinänen¹

¹Department of Biological and Environmental Sciences, Division of Biochemistry, and ²Institute of Biotechnology, Viikki Biocenter, University of Helsinki, FI-00014 Helsinki, Finland, and ³Institute of Biomedicine, Division of Pharmacology, Biomedicum Helsinki, University of Helsinki, FI-00290 Helsinki, Finland

Correspondence should be addressed to Kari Keinänen, Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, FI-00014 Helsinki, Finland. Email: kari.keinanen{at}helsinki.fi

Regulated trafficking of AMPA receptors to cell surface and to synapses is an important determinant of neuronal excitability. In the present study, we have addressed the role of agonist binding and desensitization in the early trafficking of glutamate receptor-D (GluR-D) AMPA receptors. Analysis of point-mutated GluR-D receptors, via electrophysiology and immunofluorescence, revealed that agonist-binding activity is essential for efficient delivery to cell surface in transfected cell lines and in neurons. Cotransfection with stargazin could fully rescue the surface expression of nonbinding mutant receptors in cell lines, indicating that stargazin is able to interact with and promote exit of AMPA receptors from endoplasmic reticulum (ER) independently of agonist binding. Secretion of separately expressed ligand-binding domain constructs showed a similar dependency of agonist binding to that observed with full-length GluR-D, supporting the idea that glutamate-induced closure of the binding site cleft is registered by ER quality control as a necessary priming step for transport competence. In contrast to agonist binding, the ability of the receptor to undergo desensitization had only a minor influence on trafficking. Our results are consistent with the hypothesis that AMPA receptors are synthesized as intrinsically unstable molecules, which require glutamate binding for structural stability and for transport-competence.

Key words: AMPA receptor; ER exit; GluR-D; GluR4; receptor transport; stargazin

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Received Aug. 19, 2008; revised Oct. 23, 2008; accepted Nov. 26, 2008.

Correspondence should be addressed to Kari Keinänen, Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, FI-00014 Helsinki, Finland. Email: kari.keinanen{at}helsinki.fi

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