GLUD2

Abstract: Publisher Summary Glutamate dehydrogenases, as a class, catalyze the reversible oxidative deamination of L-glutamate to α -ketoglutarate and ammonia The description of the characteristics of this reaction from a variety of sources show that, although all classed as glutamate dehydrogenase, the enzymes are different in terms of kinetic characteristics, metabolic function, and molecular properties The animal enzymes are sensitive to the concentration of purine nucleotides, can catalyze the reaction using either Nicotinamide adenine dinucleotide (NAD) or Nicotinamide adenine dinucleotide phosphate (NADP), and undergo a reversible polymerization reaction, which might influence the allosteric characteristics of the enzyme The non-animal sources are specific either for NAD or for NADP, are in general not influenced by purine nucleotides, and do not appear to undergo a reversible polymerization reaction These differences are related to the metabolic role of the reaction, which in animal tissues serves as an important link between carbohydrate and protein metabolism utilizing either α-ketoglutarate or glutamate depending on the condition of the cell, but which in non-animal organisms might act unidirectionally

Abstract: Cbln1, secreted from cerebellar granule cells, and the orphan glutamate receptor delta2 (GluD2), expressed by Purkinje cells, are essential for synapse integrity between these neurons in adult mice. Nevertheless, no endogenous binding partners for these molecules have been identified. We found that Cbln1 binds directly to the N-terminal domain of GluD2. GluD2 expression by postsynaptic cells, combined with exogenously applied Cbln1, was necessary and sufficient to induce new synapses in vitro and in the adult cerebellum in vivo. Further, beads coated with recombinant Cbln1 directly induced presynaptic differentiation and indirectly caused clustering of postsynaptic molecules via GluD2. These results indicate that the Cbln1-GluD2 complex is a unique synapse organizer that acts bidirectionally on both pre- and postsynaptic components.

Abstract: Cbln1 is a cerebellum-specific protein of previously unknown function that is structurally related to the C1q and tumor necrosis factor families of proteins. We show that Cbln1 is a glycoprotein secreted from cerebellar granule cells that is essential for three processes in cerebellar Purkinje cells: the matching and maintenance of pre- and postsynaptic elements at parallel fiber–Purkinje cell synapses, the establishment of the proper pattern of climbing fiber–Purkinje cell innervation, and induction of long-term depression at parallel fiber–Purkinje cell synapses. Notably, the phenotype of cbln1-null mice mimics loss-of-function mutations in the orphan glutamate receptor, GluRδ2, a gene selectively expressed in Purkinje neurons. Therefore, Cbln1 secreted from presynaptic granule cells may be a component of a transneuronal signaling pathway that controls synaptic structure and plasticity.

Abstract: The glutamate receptor δ2 subunit (GluRδ2) is specifically expressed in cerebellar Purkinje cells (PCs) from early developmental stages and is selectively localized at dendritic spines forming synapses with parallel fibers (PFs). Targeted disruption of the GluRδ2 gene leads to a significant reduction of PF→PC synapses. To address its role in the synaptogenesis, the morphology and electrophysiology of PF→PC synapses were comparatively examined in developing GluRδ2 mutant and wild-type cerebella. PCs in GluRδ2 mutant mice were normally produced, migrated, and formed spines, as did those in wild-type mice. At the end of the first postnatal week, 74–78% of PC spines in both mice formed immature synapses, which were characterized by small synaptic contact, few synaptic vesicles, and incomplete surrounding by astroglial processes, eliciting little electrophysiological response. During the second and third postnatal weeks when spines and terminals are actively generated, the percentage of PC spines forming synapses attained 98–99% in wild type but remained as low as 55–60% in mutants, and the rest were unattached to any nerve terminals. As a result, the number of PF synapses per single-mutant PCs was reduced to nearly a half-level of wild-type PCs. Parallelly, PF stimulation less effectively elicited EPSCs in mutant PCs than in wild-type PCs during and after the second postnatal week. These results suggest that the GluRδ2 is involved in the stabilization and strengthening of synaptic connectivity between PFs and PCs, leading to the association of all PC spines with PF terminals to form functionally mature synapses.