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      Granuphilin molecularly docks insulin granules to the fusion machinery

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          Abstract

          The Rab27a effector granuphilin is specifically localized on insulin granules and is involved in their exocytosis. Here we show that the number of insulin granules morphologically docked to the plasma membrane is markedly reduced in granuphilin-deficient β cells. Surprisingly, despite the docking defect, the exocytosis of insulin granules in response to a physiological glucose stimulus is significantly augmented, which results in increased glucose tolerance in granuphilin-null mice. The enhanced secretion in mutant β cells is correlated with a decrease in the formation of the fusion-incompetent syntaxin-1a–Munc18-1 complex, with which granuphilin normally interacts. Furthermore, in contrast to wild-type granuphilin, its mutant that is defective in binding to syntaxin-1a fails to restore granule docking or the protein level of syntaxin-1a in granuphilin-null β cells. Thus, granuphilin not only is essential for the docking of insulin granules but simultaneously imposes a fusion constraint on them through an interaction with the syntaxin-1a fusion machinery. These findings provide a novel paradigm for the docking machinery in regulated exocytosis.

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          Most cited references37

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          RADIOAUTOGRAPHIC STUDIES OF CHOLINE INCORPORATION INTO PERIPHERAL NERVE MYELIN

          This radioautographic study was designed to localize the cytological sites involved in the incorporation of a lipid precursor into the myelin and the myelin-related cell of the peripheral nervous system. Both myelinating and fully myelinated cultures of rat dorsal root ganglia were exposed to a 30-min pulse of tritiated choline and either fixed immediately or allowed 6 or 48 hr of chase incubation before fixation. After Epon embedding, light and electron microscopic radioautograms were prepared with Ilford L-4 emulsion. Analysis of the pattern of choline incorporation into myelinating cultures indicated that radioactivity appeared all along the length of the internode, without there being a preferential site of initial incorporation. Light microscopic radioautograms of cultures at varying states of maturity were compared in order to determine the relative degree of myelin labeling. This analysis indicated that the myelin-Schwann cell unit in the fully myelinated cultures incorporated choline as actively as did this unit in the myelinating cultures. Because of technical difficulties, it was not possible to determine the precise localization of the incorporated radioactivity within the compact myelin. These data are related to recent biochemical studies indicating that the mature myelin of the central nervous system does incorporate a significant amount of lipid precursor under the appropriate experimental conditions. These observations support the concept that a significant amount of myelin-related metabolic activity occurs in mature tissue; this activity is considered part of an essential and continuous process of myelin maintenance and repair.
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            HPRT-deficient (Lesch-Nyhan) mouse embryos derived from germline colonization by cultured cells.

            Embryonal stem (ES) cell lines, established in culture from peri-implantation mouse blastocysts, can colonize both the somatic and germ-cell lineages of chimaeric mice following injection into host blastocysts. Recently, ES cells with multiple integrations of retroviral sequences have been used to introduce these sequences into the germ-line of chimaeric mice, demonstrating an alternative to the microinjection of fertilized eggs for the production of transgenic mice. However, the properties of ES cells raise a unique possibility: that of using the techniques of somatic cell genetics to select cells with genetic modifications such as recessive mutations, and of introducing these mutations into the mouse germ line. Here we report the realization of this possibility by the selection in vitro of variant ES cells deficient in hypoxanthine guanine phosphoribosyl transferase (HPRT; EC 2.4.2.8), their use to produce germline chimaeras resulting in female offspring heterozygous for HPRT-deficiency, and the generation of HPRT-deficient preimplantation embryos from these females. In human males, HPRT deficiency causes Lesch-Nyhan syndrome, which is characterized by mental retardation and self-mutilation.
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              Synaptic vesicle pools.

              Communication between cells reaches its highest degree of specialization at chemical synapses. Some synapses talk in a 'whisper'; others 'shout'. The 'louder' the synapse, the more synaptic vesicles are needed to maintain effective transmission, ranging from a few hundred (whisperers) to nearly a million (shouters). These vesicles reside in different 'pools', which have been given a bewildering array of names. In this review, we focus on five tissue preparations in which synaptic vesicle pools have been identified and thoroughly characterized. We argue that, in each preparation, each vesicle can be assigned to one of three distinct pools.
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                Author and article information

                Journal
                J Cell Biol
                JCB
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                10 October 2005
                : 171
                : 1
                : 99-109
                Affiliations
                [1 ]Laboratory of Molecular Endocrinology and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, Japan
                [2 ]Laboratory for Behavioral Genetics, Brain Science Institute, Institute of Physical and Chemical Research, Saitama 351-0198, Japan
                Author notes

                Correspondence to Tetsuro Izumi: tizumi@ 123456showa.gunma-u.ac.jp

                Article
                200505179
                10.1083/jcb.200505179
                2171228
                16216924
                6f718a1b-fa23-46a4-b4f6-fc185095de53
                Copyright © 2005, The Rockefeller University Press
                History
                : 31 May 2005
                : 6 September 2005
                Categories
                Research Articles
                Article

                Cell biology
                Cell biology

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