GRM1

GRM1 is the gene encoding metabotropic glutamate receptor 1 (mGluR1), a member of the class C family of G protein–coupled receptors. mGluR1 is activated by glutamate and couples to Gq/11 proteins, triggering phospholipase Cβ signaling, IP3 and DAG production, and intracellular calcium release, which modulates neuronal excitability and synaptic plasticity.

In the brain, GRM1 is highly expressed in cerebellar Purkinje cells, with substantial distribution in the cortex and hippocampus. Through mGluR1 signaling, it contributes to synaptic plasticity and learning, including cerebellar long-term depression at parallel fiber-Purkinje cell synapses, which underpins motor coordination and motor learning.

Genetic variants in GRM1 have been associated with spinocerebellar ataxia type 44 (SCA44) and related movement disorders, typically presenting with progressive ataxia, dysarthria, and oculomotor abnormalities. Other rare GRM1 variants have been implicated in neurodevelopmental phenotypes, including seizures or intellectual disability, though evidence is limited and ongoing.

Animal models lacking GRM1 display motor coordination deficits and abnormal cerebellar signaling; conversely, pharmacological modulation of mGluR1, using agonists, antagonists, or allosteric modulators, has been investigated in preclinical studies to understand receptor function and potential therapeutic applications for movement disorders and neuropsychiatric conditions. Therapeutic strategies targeting mGluR1 remain under investigation.