Claudin 24-A novel enhancer of AMPA receptor fidelity.

High-fidelity fast excitatory neurotransmission in the mammalian central nervous system is conducted by the AMPA receptor (AMPAR) subfamily of ionotropic glutamate receptors. AMPARs exist as complexes of the pore-lining α subunits GluA1-4 and a number of auxiliary subunits shaping their functional properties. The first discovered family of auxiliary subunits comprises the transmembrane AMPAR regulatory proteins (TARPs). Together with germ cell-specific gene 1-like (GSG1L), they belong to the PMP-22/EMP/MP20/claudin superfamily sharing substantial sequence homology and a 4-transmembrane domain (4-TMD) topology. Here, we identify the claudin Cldn24 as a novel AMPAR auxiliary subunit in cerebellar granule cells (CGCs). Specifically accelerating the recovery of desensitized receptors, Cldn24 counterbalances gating modulation of GluA by TARP-γ2 and GSG1L in CGCs and hence enables fast reactivation of native receptors. These features substantially expand the tuning properties of hitherto known AMPAR auxiliary subunits and render Cldn24 a powerful enhancer of AMPAR fidelity.