In the brain fastexcitatory neurotransmission is mediated by ionotropic glutamate receptors(iGluRs).
Dysfunction of glutamatergicneurotransmission has been implicated with many diseases including epilepsy,autism, ischemic brain damage, and neurodevelopmental diseases such asAlzheimer’s and Parkinson’s disease 1. Since the first indications thatglutamate is a neurotransmitter in the brain 2, the study of excitatoryneurotransmission has undergone many major breakthroughs including cloning andidentifying the 18 major subunits of glutamate receptors found in the human CNS3. These receptors are organized into 4 differentfamilies called AMPA (GluA1-4), kainate (GluK1-5), NMDA (GluN1, GluN2A-D, andGluN3A,B) and delta-type (GluD1,2) receptors 3.
Under basal synaptic transmission AMPAreceptors (AMPAR) are the predominant iGluR at most excitatory synapses, withsmaller contributions coming from kainate (KAR) and NMDA receptors (NMDAR) 4. AMPARs, like other iGluRs are composedof tetramers of subunits consisting of a dimer of dimers 5. They can form both heteromeric orhomomeric complexes and their stoichiometry is important for determining AMPAR function3.
Recent breakthroughs haveshown that AMPARs have additional auxiliary subunits including thetransmembrane AMPAR receptor regulatory protein (TARP) and cornichon (CNIH)families 6. These auxiliary proteins have been demonstrated to important forappropriate receptor trafficking in neurons and for modifying the ion channelresponses to agonists 6. Absence of auxiliary proteins results in dramatically reduced AMPARcurrents due to a lack of surface trafficking 7. Recent advances have revealed that thedifferent characteristics that TARPs confer on AMPARs, specifically thetrafficking and biophysical properties, are mediated by distinct structuralelements 8. This raises an intriguing question aboutthe properties of AMPAR-auxiliary complexes in the CNS which we plan to addresswith the following three aims. As the synaptic properties is in part determinedby the specific AMPAR subunits and their auxiliary proteins expressed theresults from these aims will be of great interest to the neuroscience field 3.