Metabotropic glutamate (mGlu) receptor protomers can heterodimerize, leading to different pharmacology compared to their homodimeric counterparts. This study uses complemented donor-acceptor resonance energy transfer (CODA-RET) technology, targeted mutagenesis, and computational docking to elucidate the mechanism of activation and differential pharmacology in mGlu₂₄ heteromers. The research demonstrates that mGlu₄ PAMs binding to an upper allosteric pocket are active in both mGlu₄₄ homomers and mGlu₂₄ heteromers, while those binding a lower pocket are only efficacious in homomers. Both protomers of mGlu₂₄ heteromers are cis-activated by their orthosteric agonists, signaling independently. Intriguingly, upper pocket mGlu₄ PAMs enable trans-activation from mGlu₄ to mGlu₂, enhancing mGlu₂ cis-activation. Conversely, mGlu₂ PAMs only enhance mGlu₂ cis-activation without trans-activation. These findings offer crucial insights into the molecular logic of mGlu receptor heteromers and their potential for precision therapies.

Xin Lin, Davide Provasi, Colleen M. Niswender, Wesley B. Asher, Jonathan A. Javitch