Structure and organization of AMPA receptor-TARP complexes in the mammalian cerebellum
- Alexander M. Scrutton
- Nayanika Sengupta
- Josip Ivica
- Imogen Stockwell
- Sew Peak-Chew
- Bishal Singh
- Kunimichi Suzuki
- Veronica T. Chang
- Stephen H. McLaughlin
- James M. Krieger
- A. Radu Aricescu
- Ingo H. Greger
2025-12-11
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.