Molecular dissection of the interaction between the AMPA receptor and cornichon homolog-3.
- Authors
- Shanks, Natalie F; Cais, Ondrej; Maruo, Tomohiko; Savas, Jeffrey N; Zaika, Elena I; Azumaya, Caleigh M; Yates, John R; Greger, Ingo; Nakagawa, Terunaga
- Year
- 2014
- Journal
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- PMID
- 25186755
- DOI
- 10.1523/JNEUROSCI.0595-14.2014
- PMCID
- PMC4152608
Cornichon homologs (CNIHs) are AMPA-type glutamate receptor (AMPAR) auxiliary subunits that modulate AMPAR ion channel function and trafficking. Mechanisms underlying this interaction and functional modulation of the receptor complex are currently unclear. Here, using proteins expressed from mouse and rat cDNA, we show that CNIH-3 forms a stable complex with tetrameric AMPARs and contributes to the transmembrane density in single-particle electron microscopy structures. Peptide array-based screening and in vitro mutagenesis identified two clusters of conserved membrane-proximal residues in CNIHs that contribute to AMPAR binding. Because CNIH-1 binds to AMPARs but modulates gating at a significantly lower magnitude compared with CNIH-3, these conserved residues mediate a direct interaction between AMPARs and CNIHs. In addition, residues in the extracellular loop of CNIH-2/3 absent in CNIH-1/4 are critical for both AMPAR interaction and gating modulation. On the AMPAR extracellular domains, the ligand-binding domain and possibly a stretch of linker, connecting the ligand-binding domain to the fourth membrane-spanning segment, is the principal contact point with the CNIH-3 extracellular loop. In contrast, the membrane-distal N-terminal domain is less involved in AMPAR gating modulation by CNIH-3 and AMPAR binding to CNIH-3. Collectively, our results identify conserved residues in the membrane-proximal region of CNIHs that contribute to AMPAR binding and an additional unique segment in the CNIH-2/3 extracellular loop required for both physical interaction and gating modulation of the AMPAR. Consistent with the dissociable properties of binding and gating modulation, we identified a mutant CNIH-3 that preserves AMPAR binding capability but has attenuated activity of gating modulation.
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External
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|---|---|---|---|---|
| Trafficking of the human Na<sup>+</sup>/H<sup>+</sup> antiporter NHA2 to the plasma membrane requires cornichon COPII cargo receptors. | KacovskΓ‘ K et al. | β | 2026 | β |
| Integrated multi-omic characterizations of the synapse reveal RNA processing factors and ubiquitin ligases associated with neurodevelopmental disorders. | Mei Y et al. | β | 2025 | β |
| Unravelling the genetic complexity of drug-resistant epilepsy: a critical narrative review. | Giacon M et al. | β | 2025 | β |
| The Role of Cornichons in the Biogenesis and Functioning of Monovalent-Cation Transport Systems. | PapouΕ‘kovΓ‘ K et al. | β | 2024 | β |
| Transcriptomic profile of premature ovarian insufficiency with RNA-sequencing. | Wu J et al. | β | 2024 | β |
| Comprehensive analysis of clinical prognosis and biological significance of CNIH4 in cervical cancer. | Wang J et al. | β | 2023 | β |
| Differential regulation of tetramerization of the AMPA receptor glutamate-gated ion channel by auxiliary subunits. | Certain N et al. | β | 2023 | β |
| <i>Cnih3</i> Deletion Dysregulates Dorsal Hippocampal Transcription across the Estrous Cycle. | Mulvey B et al. | β | 2023 | β |
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