Stargazin modulates AMPA receptor gating and trafficking by distinct domains

Abstract

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors mediate fast excitatory synaptic transmission in the brain. These ion channels rapidly deactivate and desensitize, which determine the time course of synaptic transmission. Here, we find that the AMPA receptor interacting protein, stargazin, not only mediates AMPA receptor trafficking but also shapes synaptic responses by slowing channel deactivation and desensitization. The cytoplasmic tail of stargazin determines receptor trafficking, whereas the ectodomain controls channel properties. Stargazin alters AMPA receptor kinetics by increasing the rate of channel opening. Disrupting the interaction of stargazin ectodomain with hippocampal AMPA receptors alters the amplitude and shape of synaptic responses, establishing a crucial function for stargazin in controlling the efficacy of synaptic transmission in the brain.

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Figure 1: Stargazin enhances glutamate-evoked currents in Xenopus laevis oocytes injected with GluR1.
Figure 2: Stargazin mediates AMPAR trafficking and also modulates AMPAR agonist efficacy.
Figure 3: Stargazin regulates AMPAR trafficking and agonist efficacy by distinct mechanisms.
Figure 4: Stargazin slows AMPAR desensitization and deactivation.
Figure 5: Stargazin increases AMPAR open channel probability.
Figure 6: The ectodomain of stargazin influences the amplitude and decay of EPSCs in hippocampal neurons.

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Acknowledgements

The authors thank K. Kam for help with analysing mEPSCs; A. Tzingounis for discussions; A. Sui for technical assistance; and R Moberg for help with preparation of the manuscript. D.S.B. is supported by grants from the National Institutes of Health, the Christopher Reeve Paralysis Foundation and the Human Frontier Science Program. R.A.N. is supported by grants from NIH. J.R.H. is supported by grants from NIH. K.W. is supported by grants from Grants-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan, and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. D.S.B. is an established investigator of the American Heart Association. R.A.N. is a member of the Keck Center for Integrative Neuroscience and the Silvio Conte Center for Neuroscience Research. S.T. is supported by a grant from NIH. H.A. is a Howard Hughes Medical Institute predoctoral fellow.

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Correspondence to Roger A. Nicoll or David S. Bredt.

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Supplementary information

Supplementary Figure S1

Stargazin does not change the I-V relationship for homomeric GluR1 flip (GluR1i) or heteromeric (GluR1i/GluR2i) AMPA receptors. (JPG 56 kb)

Supplementary Figure S2

Overexpression of wild-type stargazin does not affect the decay kinetics (a) or amplitude (b) of hippocampal mEPSCs. (JPG 76 kb)

Supplementary Figure S3

The ectodomain of stargazin is necessary to properly restore the time course and amplitude of synaptic currents in stg (-/-) cerebellar granules cells. (JPG 72 kb)

Supplementary Figure Legends

Legends to accompany the above Supplementary Figures. (DOC 22 kb)

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Tomita, S., Adesnik, H., Sekiguchi, M. et al. Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435, 1052–1058 (2005). https://doi.org/10.1038/nature03624

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