Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer

• Published in: Nature communications 2024-10, Vol.15 (1), p.8552-15, Article 8552
• Main Authors: Lin, Xin, Provasi, Davide, Niswender, Colleen M., Asher, Wesley B., Javitch, Jonathan A.
• Format: Article
• Language: English
• Subjects: 13/106; 13/95; 631/378/340; 631/45/612/194; 631/535/1267; 631/57/2272/2276; 631/92/436/2387; 96/109; 96/35; Allosteric properties; Allosteric Regulation; Allosteric Site; Animals; Energy transfer; Glutamic acid receptors (metabotropic); HEK293 Cells; Humanities and Social Sciences; Humans; Mental disorders; Molecular Docking Simulation; multidisciplinary; Neuromodulation; Pharmacology; Protein Multimerization; Receptors; Receptors, Metabotropic Glutamate - chemistry; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Science; Science (multidisciplinary); Signal Transduction; Site-directed mutagenesis; Transmembrane domains
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52822-4

Metabotropic glutamate (mGlu) receptor protomers can heterodimerize, leading to different pharmacology compared to their homodimeric counterparts. Here, we use complemented donor-acceptor resonance energy transfer (CODA-RET) technology that distinguishes signaling from defined mGlu heterodimers or homodimers, together with targeted mutagenesis of receptor protomers and computational docking, to elucidate the mechanism of activation and differential pharmacology in mGlu 2/4 heteromers. We demonstrate that positive allosteric modulators (PAMs) that bind an upper allosteric pocket in the mGlu 4 transmembrane domain are active at both mGlu 4/4 homomers and mGlu 2/4 heteromers, while those that bind a lower allosteric pocket within the same domain are efficacious in homomers but not heteromers. We further demonstrate that both protomers of mGlu 2/4 heteromers are cis-activated by their orthosteric agonists, signaling independently with no trans-activation detected. Intriguingly, however, upper pocket mGlu 4 PAMs enable trans-activation in mGlu 2/4 heteromers from mGlu 4 to the mGlu 2 protomer and also enhance cis-activation of the mGlu 2 protomer. While mGlu 2  PAMs enhanced mGlu 2 cis-activation in the heterodimer, we were unable to detect trans-activation in the opposite direction from mGlu 2 to the mGlu 4 protomer, suggesting an asymmetry of signaling. These insights into the molecular logic of this receptor heteromer are critical to building toward precision targeted therapies for multiple neuropsychiatric disorders. Metabotropic glutamate (mGlu) receptors form both homo- and heterodimers that respond to ligands differently. Here, the authors elucidate the mechanism of activation and differential pharmacology in mGlu 2/4 heteromers, which may guide targeted therapy.