What does it take to gate AMPA receptors?

Area of Science:

• Neuroscience
• Molecular Biology
• Biophysics

Background:

• Ionotropic glutamate receptors (IGRs) gate upon agonist binding to their ligand-binding domain.
• A specific mutation in the second transmembrane domain can also initiate receptor gating.
• This 'lurcher' mutation in delta2 glutamate receptor subunits causes spontaneous channel activity and ataxia in mice.

Purpose of the Study:

• To investigate the mechanism by which lurcher mutations alter IGR gating.
• To determine if introducing lurcher-like properties into AMPA receptors (GluR1) mimics the aberrant gating.
• To explore the functional similarity between lurcher mutations and TARP proteins in receptor gating.

Main Methods:

• Introduction of the lurcher mutation into the GluR1 AMPA receptor subunit.
• Characterization of gating properties, including glutamate potency and antagonist behavior.
• Engineering a GluR1 mutant by incorporating delta2 amino acids preceding the first transmembrane domain.

Main Results:

• The lurcher mutation in GluR1 increased glutamate potency and caused antagonists to act as partial agonists.
• A GluR1 mutant incorporating delta2 amino acids exhibited lurcher-typical gating characteristics.
• Lurcher-like mutations were proposed to enhance gating by destabilizing the receptor's closed state.

Conclusions:

• Lurcher mutations and TARPs may act as 'gating enhancers' for ionotropic glutamate receptors.
• Destabilization of the closed state by lurcher mutations allows minimal ligand-binding domain conformational changes to initiate gating.
• This mechanism explains spontaneous currents and partial agonist activity of antagonists in lurcher-like channels.