M6a acts as a nerve growth factor-gated Ca2+ channel in neuronal differentiation

Mukobata, S; Hibino, Taku; Sugiyama, Akinori; Urano, Yumiko; A, Inatomi; Kanai, Yoshikatsu; Endo, Hisako; Tashiro, Fumio

doi:10.1016/s0006-291x(02)02284-2

Cited by 59 publications

(67 citation statements)

References 29 publications

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“…Our present results imply that anti-PLP antibodies that may arise in association with epitope spreading following myelin damage could simultaneously cross-react with neurons in vivo. The possible functional consequences of cross-reactivity of antibodies to pgf epitopes are suggested by the demonstration that an anti-M6 mAb inhibits neurite extension of mouse brain cells (Lagenaur et al, 1992) and suppresses neuronal differentiation of M6-transfected PC12 cells (Mukobata et al, 2002). We have also found that some of the anti-PLP mAbs generated in the present study inhibit neurite outgrowth in vitro (unpublished observations).…”

Section: Implications For Mssupporting

confidence: 59%

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

Greenfield¹,

Reddy²,

Lees³

et al. 2006

J of Neuroscience Research

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Myelin proteolipid protein (PLP), the major protein of mammalian CNS myelin, is a member of the proteolipid gene family (pgf). It is an evolutionarily conserved polytopic integral membrane protein and a potential autoantigen in multiple sclerosis (MS). To analyze antibody recognition of PLP epitopes in situ, monoclonal antibodies (mAbs) specific for different regions of human PLP (50–69, 100–123, 139–151, 178–191, 200–219, 264–276) were generated and used to immunostain CNS tissues of representative vertebrates. mAbs to each region recognized whole human PLP on Western blots; the anti‐100–123 mAb did not recognize DM‐20, the PLP isoform that lacks residues 116–150. All of the mAbs stained fixed, permeabilized oligodendrocytes and mammalian and avian CNS tissue myelin. Most of the mAbs also stained amphibian, teleost, and elasmobranch CNS myelin despite greater diversity of their pgf myelin protein sequences. Myelin staining was observed when there was at least 40% identity of the mAb epitope and known pgf myelin proteins of the same or related species. The pgf myelin proteins of teleosts and elasmobranchs lack 116–150; the anti‐100–123 mAb did not stain their myelin. In addition to myelin, the anti‐178–191 mAb stained many neurons in all species; other mAbs stained distinct neuron subpopulations in different species. Neuronal staining was observed when there was at least approximately 30% identity of the PLP mAb epitope and known pgf neuronal proteins of the same or related species. Thus, anti‐human PLP epitope mAbs simultaneously recognize CNS myelin and neurons even without extensive sequence identity. Widespread anti‐PLP mAb recognition of neurons suggests a novel potential pathophysiologic mechanism in MS patients, i.e., that anti‐PLP antibodies associated with demyelination might simultaneously recognize pgf epitopes in neurons, thereby affecting their functions. © 2006 Wiley‐Liss, Inc.

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Section: Implications For Mssupporting

confidence: 59%

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

Greenfield¹,

Reddy²,

Lees³

et al. 2006

J of Neuroscience Research

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“…Previous reports have suggested that M6a protein could play a role in neurite outgrowth͞ extension, although this hypothesis arose from indirect evidence using antibodies against M6a in cultured cerebellar neurons (12) and on PC12 cells (13). Here we show that overexpression of M6a in developing hippocampal neurons stimulates the formation of neurites.…”

Section: M6a Is Involved In Neurite Outgrowth and Filopodium͞spine Dymentioning

confidence: 61%

“…M6a might also be interacting with other membrane proteins, as was found, for example, for the related protein PLP, which was shown to form a complex with integrins in oligodendrocytes (10). A previous work (13) has suggested that M6a could act as a Ca 2ϩ channel in PC12 cells. If this is the case, changes in M6a levels could result in different intracellular calcium ion concentrations leading to the activation of molecular pathways downstream to this second messenger.…”

Section: M6a Is Involved In Neurite Outgrowth and Filopodium͞spine Dymentioning

confidence: 77%

“…Despite M6a identification years ago (12) and its prominent expression in the CNS, little is known about its biological function. A previous study reported that overexpression of M6a in rat pheochromocytoma PC12 cells results in increased responsiveness to nerve growth factor-induced differentiation (13). In the present study, we first examined endogenous expression of M6a and then analyzed the morphological effects of the overexpression and knockdown of M6a in hippocampal neurons as well as in cell lines.…”

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confidence: 94%

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The stress-regulated protein M6a is a key modulator for neurite outgrowth and filopodium/spine formation

Alfonso

Fernández

Cooper

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

105

173

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Neuronal remodeling is a fundamental process by which the brain responds to environmental influences, e.g., during stress. In the hippocampus, chronic stress causes retraction of dendrites in CA3 pyramidal neurons. We have recently identified the glycoprotein M6a as a stress-responsive gene in the hippocampal formation. This gene is down-regulated in the hippocampus of both socially and physically stressed animals, and this effect can be reversed by antidepressant treatment. In the present work, we analyzed the biological function of the M6a protein. Immunohistochemistry showed that the M6a protein is abundant in all hippocampal subregions, and subcellular analysis in primary hippocampal neurons revealed its presence in membrane protrusions (filopodia͞ spines). Transfection experiments revealed that M6a overexpression induces neurite formation and increases filopodia density in hippocampal neurons. M6a knockdown with small interference RNA methodology showed that M6a low-expressing neurons display decreased filopodia number and a lower density of synaptophysin clusters. Taken together, our findings indicate that M6a plays an important role in neurite͞filopodium outgrowth and synapse formation. Therefore, reduced M6a expression might be responsible for the morphological alterations found in the hippocampus of chronically stressed animals. Potential mechanisms that might explain the biological effects of M6a are discussed. chronic stress ͉ hippocampus T he adult nervous system can be strongly influenced by sensory input from the outside environment. For example, prolonged exposure to adverse situations can have severe consequences for the brain, conferring susceptibility to certain psychiatric disorders. Indeed, chronic stress is one of the main factors known to trigger depression in humans (1). One of the most extensively studied regions in the brain is the hippocampal formation, which possesses a remarkable degree of plasticity and is particularly sensitive to stress. Studies in rodents and tree shrews demonstrated that chronic stress can cause alterations in neuronal processes. Stressed animals show morphological changes in CA3 pyramidal neurons, characterized by a reduction of apical dendritic branching and total dendritic length (2, 3). In addition, stressed rats also display a marked retraction of thorny excrescences and reduced synaptic density (4-6). Interestingly, antidepressant treatment can block these stress effects (7). Although there has been important progress regarding the understanding of the stress response and antidepressant action, the molecular pathways underlying these plastic alterations still remain largely unknown.By using subtractive hybridization libraries, we have recently identified the gene encoding the glycoprotein M6a as a stressresponsive gene. Expression levels for M6a are decreased in hippocampal tissue of tree shrews subjected to chronic psychosocial stress, and this down-regulation is prevented by chronic administration of the antidepressant clomipramine (8). Moreover, mice exp...

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“…It is generally believed that glycoproteins of the PLP family function as structural proteins for myelination. M6a, however, is also thought to function as a modulator for neurite outgrowth [28] and spine formation [29], and also acts as a nerve growth factor-gated Ca 2+ channel in neuronal differentiation [30]. The Co-localization and co-internalization of M6a and MOPr in cortical neurons.…”

Section: Discussionmentioning

confidence: 99%

Membrane glycoprotein M6A promotes μ-opioid receptor endocytosis and facilitates receptor sorting into the recycling pathway

Liang

Stumm

et al. 2008

Cell Res

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The interaction of μ-opioid receptor (MOPr) with the neuronal membrane glycoprotein M6a is known to facilitate MOPr endocytosis in human embryonic kidney 293 (HEK293) cells. To further study the role of M6a in the post-endocytotic sorting of MOPr, we investigated the agonist-induced co-internalization of MOPr and M6a and protein targeting after internalization in HEK293 cells that co-expressed HA-tagged MOPr and Myc-tagged M6a. We found that M6a, MOPr, and Rab 11, a marker for recycling endosomes, co-localized in endocytotic vesicles, indicating that MOPr and M6a are primarily targeted to recycling endosomes after endocytosis. Furthermore, co-expression of M6a augmented the post-endocytotic sorting of δ-opioid receptors into the recycling pathway, indicating that M6a might have a more general role in opioid receptor post-endocytotic sorting. The enhanced post-endocytotic sorting of MOPr into the recycling pathway was accompanied by a decrease in agonist-induced receptor down-regulation of M6a in co-expressing cells. We tested the physiological relevance of these findings in primary cultures of cortical neurons and found that co-expression of M6a markedly increased the translocation of MOPrs from the plasma membrane to intracellular vesicles at steady state and significantly enhanced both constitutive and agonist-induced receptor endocytosis. In conclusion, our results strongly indicate that M6a modulates MOPr endocytosis and post-endocytotic sorting and has an important role in receptor regulation.

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M6a acts as a nerve growth factor-gated Ca2+ channel in neuronal differentiation

Cited by 59 publications

References 29 publications

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

Monoclonal antibodies to distinct regions of human myelin proteolipid protein simultaneously recognize central nervous system myelin and neurons of many vertebrate species

The stress-regulated protein M6a is a key modulator for neurite outgrowth and filopodium/spine formation

Membrane glycoprotein M6A promotes μ-opioid receptor endocytosis and facilitates receptor sorting into the recycling pathway

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