Transmembrane AMPAR Regulatory Protein y-2 Is Required for the Modulation of XXXX Release by Presynaptic AMPARs.

@entity2227 @entity1246 @entity11272 @entity19 @entity1023 @entity140 @entity10640
Presynaptic ionotropic @entity2227 receptors (iGluRs) play important roles in the control of synaptogenesis and neurotransmitter release, yet their regulation is poorly understood. In particular, the contribution of transmembrane auxiliary proteins, which profoundly shape the trafficking and gating of somatodendritic iGluRs, is unknown. Here we examined the influence of transmembrane AMPAR regulatory proteins (TARPs) on presynaptic AMPARs in cerebellar molecular layer interneurons (MLIs). @entity1023 ( @entity1023 ), a partial agonist at @entity11272 -associated AMPARs, enhanced spontaneous @entity1246 release in wild-type @entity19 but not in stargazer @entity19 that lack the prototypical @entity11272 stargazin (y-2). These findings were replicated in mechanically dissociated Purkinje cells with functional adherent synaptic boutons, demonstrating the presynaptic locus of modulation. In dissociated Purkinje cells from stargazer @entity19 , @entity140 was able to enhance mIPSC frequency, but only in the presence of the positive allosteric modulator @entity10640 . Thus, ordinarily, presynaptic AMPARs are unable to enhance spontaneous release without y-2, which is required predominantly for its effects on channel gating. Presynaptic AMPARs are known to reduce action potential-driven @entity1246 release from MLIs. Although a G-protein-dependent non-ionotropic mechanism has been suggested to underlie this inhibition, paradoxically we found that y-2, and thus AMPAR gating, was required. Following @entity2227 spillover from climbing fibers or application of @entity1023 , evoked @entity1246 release was reduced; in stargazer @entity19 such effects were markedly attenuated in acute slices and abolished in the dissociated Purkinje cell-nerve bouton preparation. We suggest that y-2 association, by increasing charge transfer, allows presynaptic AMPARs to depolarize the bouton membrane sufficiently to modulate both phasic and spontaneous release.
