Organisation and activation mechanism of AMPA glutamate receptor complexes

AMPA receptor signaling underlies information processing, while receptor malfunction leads to various brain disorders, rendering them strategic drug targets. The activation of an individual receptor - the process leading to opening of the channel?s pore in response to agonist binding - involves multiple conformational transitions. Their rates and energies determine how the receptor processes information. Activation is modulated by auxiliary proteins that are expressed in region-specific patterns, and by drugs selectively targeting AMPAR subtypes. We will use cryo-EM and high-resolution single channel recordings to study activation of a predominant forebrain AMPAR complex. We will elucidate the modulatory mechanism of two major auxiliary subunits, and of leading AMPAR therapeutics in this process. We will generate cryo-EM structures of activation intermediates and of native AMPAR complexes derived from neuronal synapses. Together, we will lay the framework to understanding the fundamentals underlying synaptic communication and the action of selective neurotherapeutics in this process.