Structure and organization of AMPA receptor-TARP complexes in the mammalian cerebellum
Alexander M. Scrutton, Nayanika Sengupta, Josip Ivica, Imogen Stockwell, Sew‐Yeu Peak‐Chew, B.K. Singh, K. Suzuki, Veronica T. Chang, Stephen H. McLaughlin, James Krieger, A.R. Aricescu, Ingo H. Greger
Abstract
AMPA receptors (AMPARs) are multimodal transducers of glutamatergic signals throughout the brain. Their diversity is exemplified in the cerebellum: At afferent synapses, AMPARs mediate high-frequency excitation, whereas in Bergmann glia (BG) they support calcium transients that modulate synaptic transmission. This spectrum arises from different combinations of core subunits (GluA1-4), auxiliary proteins, and posttranscriptional modifications. Using mass spectrometry, cryo-electron microscopy, and electrophysiology, we characterize major cerebellar AMPARs in pigs: calcium-impermeable GluA2/A4 heteromers with four transmembrane AMPAR regulatory protein (TARP) subunits, mainly neuronal in origin, and BG-specific, calcium-permeable GluA1/A4 heteromers containing two type II TARPs. We also showed that GluA4 receptors frequently exhibit compact N-terminal domains that promote their synaptic delivery. Our study defines the organizational principles of mammalian cerebellar AMPAR complexes and reveals how different receptor subtypes support cell type-specific functions.