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.