Glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) L504Y mutant (GluA2 L504Y)

The Glutamate ionotropic receptor AMPA type subunit 2 (GRIA2) L504Y mutant is a synthetic variant of the AMPA receptor subunit 2, characterized by a leucine-to-tyrosine substitution at position 504. This mutation is strategically located at the dimer interface of the ligand-binding domain (LBD) and is renowned in molecular biology for its ability to completely block receptor desensitization (Sun et al., 2002, Nature). By preventing the conformational changes that lead to the desensitized state, the L504Y mutant locks the receptor in a constitutively active or open state upon agonist binding (Armstrong et al., 2006, Neuron). This property makes it an indispensable tool for structural studies, such as X-ray crystallography and cryo-electron microscopy, allowing for the visualization of the receptor's active conformation (Sobolevsky et al., 2009, Nature). While the L504Y mutation itself is not found in human pathologies, the AMPA receptor family it represents is a major therapeutic target for neurological conditions including epilepsy, amyotrophic lateral sclerosis (ALS), and stroke (Traynelis et al., 2010, Pharmacological Reviews). Drugs interacting with this mutant include standard AMPA receptor agonists like glutamate and antagonists like perampanel, though the mutation significantly alters the receptor's kinetic response to these agents.

Other names

GluR2 L504YGluR-B L504YMutant GluR2 L504YL504Y-GluA2Desensitization-deficient GluA2

The L504Y mutation acts as a structural block to desensitization by stabilizing the ligand-binding domain dimer interface; drugs targeting the receptor act via competitive antagonism or non-competitive allosteric inhibition.