HNK-1 Glyco-epitope Regulates the Stability of the Glutamate Receptor Subunit GluR2 on the Neuronal Cell Surface

Morita, Ippei; Kakuda, Shinako; Takeuchi, Yusuke; Itoh, Seiga; Kawasaki, Nana; Kizuka, Yasuhiko; Kawasaki, Toshisuke; Oka, Shogo

doi:10.1074/jbc.m109.024208

Cited by 50 publications

(67 citation statements)

References 45 publications

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“…In addition, some proteoglycans and glycolipids are also known to bear the HNK-1 epitope [20], and in mice, the HNK-1 epitope is selectively found on myelinating Schwann cells associated with motor axons [19]. In GlcAT-P / b3gat1 knock-out mice, an almost complete loss of the HNK-1 epitope in the brain is observed [35]. In our analysis the HNK-1 epitope was still detected in immunoblots of brv mutant larval CNS, suggesting that in the fly, GlcAT-P is not required or is redundant for the generation of the HNK-1 epitope.…”

Section: Discussionmentioning

confidence: 99%

The Glucuronyltransferase GlcAT-P Is Required for Stretch Growth of Peripheral Nerves in Drosophila

2011

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During development, the growth of the animal body is accompanied by a concomitant elongation of the peripheral nerves, which requires the elongation of integrated nerve fibers and the axons projecting therein. Although this process is of fundamental importance to almost all organisms of the animal kingdom, very little is known about the mechanisms regulating this process. Here, we describe the identification and characterization of novel mutant alleles of GlcAT-P, the Drosophila ortholog of the mammalian glucuronyltransferase b3gat1. GlcAT-P mutants reveal shorter larval peripheral nerves and an elongated ventral nerve cord (VNC). We show that GlcAT-P is expressed in a subset of neurons in the central brain hemispheres, in some motoneurons of the ventral nerve cord as well as in central and peripheral nerve glia. We demonstrate that in GlcAT-P mutants the VNC is under tension of shorter peripheral nerves suggesting that the VNC elongates as a consequence of tension imparted by retarded peripheral nerve growth during larval development. We also provide evidence that for growth of peripheral nerve fibers GlcAT-P is critically required in hemocytes; however, glial cells are also important in this process. The glial specific repo gene acts as a modifier of GlcAT-P and loss or reduction of repo function in a GlcAT-P mutant background enhances VNC elongation. We propose a model in which hemocytes are required for aspects of glial cell biology which in turn affects the elongation of peripheral nerves during larval development. Our data also identifies GlcAT-P as a first candidate gene involved in growth of integrated peripheral nerves and therefore establishes Drosophila as an amenable in-vivo model system to study this process at the cellular and molecular level in more detail.

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Section: Discussionmentioning

confidence: 99%

The Glucuronyltransferase GlcAT-P Is Required for Stretch Growth of Peripheral Nerves in Drosophila

2011

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“…It was found that the HNK-1 epitope downregulates endocytosis of the AMPA glutamate receptor subunit GluR2 and stabilizes its expression on neuronal plasma membranes. Moreover, the presence of HNK-1 promotes the interaction between GluR2 and N-cadherin, which probably regulates the stability of GluR2 on the cell surface at synaptic connections (Morita et al 2009). The HNK-1 epitope is present on a number of glycoproteins involved in intracellular adhesion, cell migration and synaptic plasticity (reviewed in (Kleene and Schachner 2004, Yanagisawa and Yu 2007)).…”

Section: N-glycans In Neural Physiologymentioning

confidence: 99%

N-Glycosylation in Regulation of the Nervous System

Scott

Panin

2014

Advances in Neurobiology

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Summary Protein N-glycosylation can influence the nervous system in a variety of ways by affecting functions of glycoproteins involved in nervous system development and physiology. The importance of N-glycans for different aspects of neural development has been well documented. For example, some N-linked carbohydrate structures were found to play key roles in neural cell adhesion and axonal targeting during development. At the same time, the involvement of glycosylation in the regulation of neural physiology remains less understood. Recent studies have implicated N-glycosylation in the regulation of neural transmission, revealing novel roles of glycans in synaptic processes and the control of neural excitability. N-Glycans were found to markedly affect the function of several types of synaptic proteins involved in key steps of synaptic transmission, including neurotransmitter release, reception and uptake. Glycosylation also regulates a number of channel proteins, such as TRP channels that control responses to environmental stimuli and voltage-gated ion channels, the principal determinants of neuronal excitability. Sialylated carbohydrate structures play a particularly prominent part in the modulation of voltage gated ion channels. Sialic acids appear to affect channel functions via several mechanisms, including charge interactions, as well as other interactions that probably engage steric effects and interactions with other molecules. Experiments also indicated that some structural features of glycans can be particularly important for their function. Since glycan structures can vary significantly between different cell types and depends on the metabolic state of the cell, it is important to analyze glycan functions using in vivo approaches. While the complexity of the nervous system and intricacies of glycosylation pathways can create serious obstacles for in vivo experiments in vertebrates, recent studies have indicated that more simple and experimentally tractable model organisms like Drosophila should provide important advantages for elucidating evolutionarily conserved functions of N-glycosylation in the nervous system.

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“…Interestingly, previous studies have shown that human natural killer-1 (HNK-1) carbohydrate and polysialic acid (PSA), which are known to be covalently attached to N-linked oligosaccharides of AMPA receptors and NCAM, respectively, in the Golgi apparatus at the final step of N-glycosylation, are required for the maintenance of LTP in the hippocampal CA1 region and hippocampus-dependent memory (Becker et al, 1996;Morita et al, 2009;Senkov et al, 2006;Strekalova, Wotjak, & Schachner, 2001;Venero et al, 2006;Yamamoto et al, 2002). Therefore, it is possible that blocking N-glycosylation inhibits the addition of HNK-1 carbohydrate and PSA to those target proteins, thereby leading to impairments in memory consolidation and reconsolidation.…”

Section: Discussionmentioning

confidence: 99%

N-glycosylation in the hippocampus is required for the consolidation and reconsolidation of contextual fear memory

Inaba

Kai

Kida

2016

Neurobiology of Learning and Memory

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Memory consolidation and reconsolidation have been shown to require new gene expression. N-glycosylation, one of the major post-translational modifications, is known to play essential or regulatory roles in protein function. A previous study suggested that N-glycosylation is required for the maintenance of long-term potentiation in hippocampal CA1 neurons. However, the role of de novo N-glycosylation in learning and memory, such as memory consolidation and reconsolidation, still remains unclear. Here, we show critical roles for N-glycosylation in the consolidation and reconsolidation of contextual fear memory in mice. We examined the effects of pharmacological inhibition of N-glycosylation in the hippocampus on these memory processes using three different inhibitors (tunicamycin, 1-deoxynojirimycin, and swainsonine) that block the enzymatic activity required for N-glycosylation at different steps. Microinfusions of the N-glycosylation inhibitors into the dorsal hippocampus impaired long-term memory (LTM) formation without affecting short-term memory (STM). Similarly, this pharmacological blockade of N-glycosylation in the dorsal hippocampus also disrupted post-reactivation LTM after retrieval without affecting post-reactivation STM. Additionally, a microinfusion of swainsonine blocked c-fos induction in the hippocampus, which is observed when memory is consolidated. Our observations showed that N-glycosylation is required for the consolidation and reconsolidation of contextual fear memory and suggested that N-glycosylation contributes to the new gene expression necessary for these memory processes.

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HNK-1 Glyco-epitope Regulates the Stability of the Glutamate Receptor Subunit GluR2 on the Neuronal Cell Surface

Cited by 50 publications

References 45 publications

The Glucuronyltransferase GlcAT-P Is Required for Stretch Growth of Peripheral Nerves in Drosophila

The Glucuronyltransferase GlcAT-P Is Required for Stretch Growth of Peripheral Nerves in Drosophila

N-Glycosylation in Regulation of the Nervous System

N-glycosylation in the hippocampus is required for the consolidation and reconsolidation of contextual fear memory

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