Abstract

Ionotropic glutamate receptors (iGluRs) are critical ligand-gated ion channels that mediate the majority of fast excitatory neurotransmission in the central nervous system. Their dysfunction is implicated in a wide range of neurological and psychiatric disorders, underscoring the importance of understanding their regulatory mechanisms. This review synthesizes recent advancements in structural biology, particularly the application of cryo-electron microscopy (cryo-EM) and X-ray crystallography, to elucidate the architecture and functional dynamics of iGluRs. We detail how these high-resolution structures have provided unprecedented insights into the principles governing iGluR assembly, the mechanisms of agonist-induced activation and desensitization, and the allosteric modulation by auxiliary subunits and pharmacological agents. Key findings highlight the conformational changes within the ligand-binding and transmembrane domains that couple glutamate binding to ion channel opening. Furthermore, the structural data illuminates the binding pockets for allosteric modulators, offering a molecular blueprint for structure-based drug design. These structural insights are essential for a deeper comprehension of iGluR physiological roles and their pathological involvement, paving the way for the development of novel therapeutic strategies targeting glutamatergic signaling.