The AMPA receptor life cycle: assembly, regulation and synaptic diversity

Abstract

AMPA receptors (AMPARs) mediate the majority of fast excitatory neurotransmission in the mammalian brain. Recent structural, functional and proteomic advances have reshaped our understanding of how these receptors assemble, gate and diversify within distinct synaptic environments. Notably, AMPAR function is governed by an interlocking set of regulatory layers that include alternative splicing and RNA editing within regions of the receptor subunits responsible for gating and permeation, and direct allosteric coupling with different families of auxiliary proteins. The assembly of AMPARs through a dedicated endoplasmic reticulum biogenesis pathway ensures accurate tetramer formation and provides a regulatory checkpoint for synaptic receptor abundance. Brain development introduces additional layers of control as editing, splicing and auxiliary-subunit expression shift from embryonic to adult states, whereas interactions with extracellular proteins contribute to the organization and diversification of synaptic architecture across circuits. Thus, AMPARs are dynamic macromolecular assemblies whose diversity underlies the breadth of glutamatergic signalling in health and disease. This Review synthesizes these emerging principles, highlighting how AMPARs transition from their molecular ‘birth’ to their deployment at functionally specialized synapses. AMPA receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. Derek Bowie and colleagues describe recent advances in our understanding of the regulatory layers that operate across the lifespan of an AMPAR to govern its assembly, structure and function.