title: Unlocking the secrets of the δ2 glutamate receptor: A gatekeeper for synaptic plasticity in the cerebellum.
abstract: Long-term changes in synaptic transmission in the central nervous system, such as long-term potentiation and long-term depression (LTD), are believed to underlie learning and memory in vivo. Despite intensive research, the precise molecular mechanisms underlying these phenomena have remained unclear. LTD is most commonly caused by the endocytosis of postsynaptic AMPA-type glutamate receptors, triggered by activity-induced serine phosphorylation of the GluA2 subunit. Interestingly, cerebellar LTD, which occurs at synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells, is unique in requiring an additional type of glutamate receptor, the δ2 receptor (GluD2). Cbln1 was recently identified as a GluD2 ligand that regulates PF synapse formation and maintenance. However, how GluD2 induces downstream signaling in Purkinje cells to regulate LTD induction is unknown. We here present evidence that GluD2 reduces the tyrosine phosphorylation level of the GluA2 subunit via PTPMEG, a protein tyrosine phosphatase that binds to GluD2's C-terminus. We also found that the serine phosphorylation of GluA2, a crucial step for AMPA-receptor endocytosis, requires prior tyrosine dephosphorylation. Thus, GluD2 may serve as a gatekeeper for LTD induction by coordinating interactions between GluA2's 2 phosphorylation sites.
authors.affiliation: Department of Physiology; Keio University School of Medicine; Tokyo, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kohda
authors.affiliation: Department of Physiology; Keio University School of Medicine; Tokyo, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Kakegawa
authors.affiliation: Department of Physiology; Keio University School of Medicine; Tokyo, Japan.
authors.forename: Michisuke
authors.initials: M
authors.lastname: Yuzaki
keywords: AMPA receptor; Purkinje cell; cerebellum; endocytosis; long-term depression (LTD); protein tyrosine phosphatase; synaptic plasticity; δ2 glutamate receptor (GluD2)