Elucidating the molecular logic of a metabotropic glutamate receptor heterodimer.

ABSTRACT: 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 mGlu₄ 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 eff

SUBMITTER: Lin X 

PROVIDER: S-EPMC11450022 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature