Non-canonical internalization mechanisms of mGlu receptors

Pin, J.-P.; Cimadevila, M.; Liu, J.; Maurel, D.; Brabet, I.; Hoscar, M.; Drube, J.; Hoffmann, C.; Inoue, A.; RONDARD, p.; Lafon, P.-A.; Prezeau, L.

doi:10.1101/2025.02.13.638043

bioRxiv · 10.1101/2025.02.13.638043

Non-canonical internalization mechanisms of mGlu receptors

Pin, J.-P.·Cimadevila, M.·Liu, J.·Maurel, D.·Brabet, I.·Hoscar, M.·Drube, J.·Hoffmann, C.·Inoue, A.·RONDARD, p.·Lafon, P.-A.·Prezeau, L.

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Abstract

Cell surface density of G protein-coupled receptors (GPCRs) is tightly regulated through constitutive and agonist-induced internalization. Whereas the mechanisms of constitutive internalization remain elusive, agonist-induced internalization is accepted to involve receptor phosphorylation by GPCR kinases (GRKs), {beta}-arrestin binding and AP2 recruitment, targeting receptors to clathrin-coated pits. Dimeric class C metabotropic glutamate (mGlu1 to 8) receptors regulate synaptic transmission but their internalization process is ambiguous. Here, we used diffusion-enhanced energy transfer (DERET) to decipher their internalization kinetics. We showed that all mGlu receptors are constitutively internalized. However, only mGlu1, 5 and 3 homodimers are agonist-induced internalized, that require neither GRKs, nor {beta}-arrestins. In contrast, the constitutive internalization involves only {beta}-arrestins. This systematic study further illustrates how different class C receptors are relative to most other GPCRs, revealing non-canonical internalization mechanisms. These insights in mGlu receptor dynamics will help promoting the therapeutic action of drugs targeting mGlu receptors.

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Pin, J.-P., Cimadevila, M., Liu, J., Maurel, D., Brabet, I., Hoscar, M., Drube, J., Hoffmann, C., Inoue, A., RONDARD, p., Lafon, P.-A., Prezeau, L.. 2025-02-13. Non-canonical internalization mechanisms of mGlu receptors. https://doi.org/10.1101/2025.02.13.638043

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