Molecular determinants of glutamate receptor function
Several mental conditions have been linked to dysfunction of ionotropic glutamate receptors, especially calcium-permeable AMPARs, known for fast synaptic transmission in the central nervous system. In turn, the biophysical properties and function of AMPARs depend on their subunit composition and on auxiliary proteins such as transmembrane AMPA regulatory proteins (TARPs). These control the trafficking and gating of the AMPARs and determine the postsynaptic responses of a given synapse. Recent evidence also indicates that TARPs increase single-channel conductance and attenuate blockage by intracellular polyamines of AMPARs. Therefore, to unravel the complexity of neuronal pathways, it is of paramount importance to delineate the regulation of AMPARs. In answer to this, scientists of the EU-funded MOAMAUX (Modulation of AMPA receptor properties by auxiliary subunits) project investigated how two of these proteins, the auxiliary subunit stargazin (TARP γ-2) and carnitine palmitoyltransferase 1C (CPT1C), interact with AMPAR complexes and regulate their function. For this purpose, they modified key residues of the receptor through site-directed mutagenesis and examined the impact of stargazin on channel function and conductance. In addition, the consortium discovered that CPT1C constitutes a new functional partner of AMPARs. They found that CPT1C interacts with a specific cysteine residue on glutamate A1 AMPARs. Further electrophysiological recordings in CPT1C knockout animals underscored the importance of this auxiliary subunit on AMPAR trafficking. Taken together, the findings of the MOAMAUX project provide important knowledge on the key mechanism underlying AMPAR surface expression. The future direction of the study includes further investigation into the molecular mechanism involved in CPT1C modulation of AMPARs such as chaperone effects and palmitoylation state of the receptor. The generated data is contributing to the growing interest in AMPAR biogenesis, trafficking and channel modulation. Importantly, clinical translation of these results could aid in developing more effective treatment for mental disorders resulting from AMPAR dysfunction.
