SCA44‐ and SCAR13‐associated GRM1 mutations affect metabotropic glutamate receptor 1 function through distinct mechanisms

Background and Purpose Metabotropic glutamate receptor 1 (mGlu 1 ) is a promising therapeutic target for neurodegenerative CNS disorders including spinocerebellar ataxias (SCAs). Clinical reports have identified naturally‐occurring mGlu 1 mutations in rare SCA subtypes and linked symptoms to mGlu 1 mutations. However, how mutations alter mGlu 1 function remains unknown, as does amenability of receptor function to pharmacological rescue. Here, we explored SCA‐associated mutation effects on mGlu 1 cell surface expression, canonical signal transduction and allosteric ligand pharmacology. Experimental Approach Orthosteric agonists, positive allosteric modulators (PAMs) and negative allosteric modulators (NAMs) were assessed at two functional endpoints (iCa 2+ mobilisation and inositol 1‐phosphate IP 1 accumulation) in FlpIn Trex HEK293A cell lines expressing five mutant mGlu 1 subtypes. Key pharmacological parameters including ligand potency, affinity and cooperativity were derived using operational models of agonism and allostery. Key Results mGlu 1 mutants exhibited differential impacts on mGlu 1 expression, with a C‐terminus truncation significantly reducing surface expression. Mutations differentially influenced orthosteric ligand affinity, efficacy and functional cooperativity between allosteric and orthosteric ligands. Loss‐of‐function mutations L454F and N885del reduced orthosteric affinity and efficacy, respectively. A gain‐of‐function Y792C mutant mGlu 1 displayed enhanced constitutive activity in IP 1 assays, which manifested as reduced orthosteric agonist activity. The mGlu 1 PAMs restored glutamate potency in iCa 2+ mobilisation for loss‐of‐function mutations and mGlu 1 NAMs displayed enhanced inverse agonist activity at Y792C relative to wild‐type mGlu 1 . Conclusion and Implications Collectively, these data highlight distinct mechanisms by which mGlu 1 mutations affect receptor function and show allosteric modulators may present a therapeutic strategy to restore aberrant mGlu 1 function in rare SCA subtypes.