PIKfyve Negatively Regulates Exocytosis in Neurosecretory Cells
Regulated secretion depends upon a highly coordinated series of protein-protein and protein-lipid interactions. Two phosphoinositides, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3-phosphate, are important for the ATP-dependent priming of the secretory apparatus prior to Ca2+-depe...
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Veröffentlicht in: | The Journal of biological chemistry 2008-02, Vol.283 (5), p.2804-2813 |
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creator | Osborne, Shona L. Wen, Peter J. Boucheron, Christine Nguyen, Hao N. Hayakawa, Masahiko Kaizawa, Hiroyuki Parker, Peter J. Vitale, Nicolas Meunier, Frederic A. |
description | Regulated secretion depends upon a highly coordinated series of protein-protein and protein-lipid interactions. Two phosphoinositides, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3-phosphate, are important for the ATP-dependent priming of the secretory apparatus prior to Ca2+-dependent exocytosis. Mechanisms that control phosphoinositide levels are likely to play an important role in priming fine tuning. Here we have investigated the involvement of PIKfyve, a phosphoinositide 5-kinase that can phosphorylate phosphatidylinositol 3-phosphate to produce phosphatidylinositol 3,5-bisphosphate on large dense core vesicle exocytosis from neuroendocrine cells. PIKfyve localizes to a subpopulation of secretory granules in chromaffin and PC12 cells. Nicotine stimulation promoted recruitment of PIKfyve-EGFP onto secretory vesicles in PC12 cells. YM-201636, a selective inhibitor of PIKfyve activity, and PIKfyve knockdown by small interfering RNA potentiated secretory granule exocytosis. Overexpression of PIKfyve or its yeast orthologue Fab1p inhibited regulated secretion in PC12 cells, whereas a catalytically inactive PIKfyve mutant had no effect. These results demonstrate a novel inhibitory role for PIKfyve catalytic activity in regulated secretion and provide further evidence for a fine tuning of exocytosis by 3-phosphorylated phosphoinositides. |
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Two phosphoinositides, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3-phosphate, are important for the ATP-dependent priming of the secretory apparatus prior to Ca2+-dependent exocytosis. Mechanisms that control phosphoinositide levels are likely to play an important role in priming fine tuning. Here we have investigated the involvement of PIKfyve, a phosphoinositide 5-kinase that can phosphorylate phosphatidylinositol 3-phosphate to produce phosphatidylinositol 3,5-bisphosphate on large dense core vesicle exocytosis from neuroendocrine cells. PIKfyve localizes to a subpopulation of secretory granules in chromaffin and PC12 cells. Nicotine stimulation promoted recruitment of PIKfyve-EGFP onto secretory vesicles in PC12 cells. YM-201636, a selective inhibitor of PIKfyve activity, and PIKfyve knockdown by small interfering RNA potentiated secretory granule exocytosis. Overexpression of PIKfyve or its yeast orthologue Fab1p inhibited regulated secretion in PC12 cells, whereas a catalytically inactive PIKfyve mutant had no effect. These results demonstrate a novel inhibitory role for PIKfyve catalytic activity in regulated secretion and provide further evidence for a fine tuning of exocytosis by 3-phosphorylated phosphoinositides.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M704856200</identifier><identifier>PMID: 18039667</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Cattle ; Chromaffin Cells - physiology ; Exocytosis - physiology ; Humans ; In Vitro Techniques ; Mice ; Neurosecretory Systems - drug effects ; Neurosecretory Systems - physiology ; PC12 Cells ; Phosphatidylinositol 3-Kinases - genetics ; Phosphatidylinositol 3-Kinases - physiology ; Phosphoinositide-3 Kinase Inhibitors ; Rats ; Recombinant Proteins - genetics ; Recombinant Proteins - pharmacology ; RNA Interference ; RNA, Small Interfering - genetics ; Transfection</subject><ispartof>The Journal of biological chemistry, 2008-02, Vol.283 (5), p.2804-2813</ispartof><rights>2008 © 2008 ASBMB. Currently published by Elsevier Inc; originally published by American Society for Biochemistry and Molecular Biology.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c464t-9c7e47bcf6e167747d94d1dbaae0a90765fad3dbea4fc3e28d4f1d644dbe202b3</citedby><cites>FETCH-LOGICAL-c464t-9c7e47bcf6e167747d94d1dbaae0a90765fad3dbea4fc3e28d4f1d644dbe202b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27915,27916</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18039667$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Osborne, Shona L.</creatorcontrib><creatorcontrib>Wen, Peter J.</creatorcontrib><creatorcontrib>Boucheron, Christine</creatorcontrib><creatorcontrib>Nguyen, Hao N.</creatorcontrib><creatorcontrib>Hayakawa, Masahiko</creatorcontrib><creatorcontrib>Kaizawa, Hiroyuki</creatorcontrib><creatorcontrib>Parker, Peter J.</creatorcontrib><creatorcontrib>Vitale, Nicolas</creatorcontrib><creatorcontrib>Meunier, Frederic A.</creatorcontrib><title>PIKfyve Negatively Regulates Exocytosis in Neurosecretory Cells</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Regulated secretion depends upon a highly coordinated series of protein-protein and protein-lipid interactions. Two phosphoinositides, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3-phosphate, are important for the ATP-dependent priming of the secretory apparatus prior to Ca2+-dependent exocytosis. Mechanisms that control phosphoinositide levels are likely to play an important role in priming fine tuning. Here we have investigated the involvement of PIKfyve, a phosphoinositide 5-kinase that can phosphorylate phosphatidylinositol 3-phosphate to produce phosphatidylinositol 3,5-bisphosphate on large dense core vesicle exocytosis from neuroendocrine cells. PIKfyve localizes to a subpopulation of secretory granules in chromaffin and PC12 cells. Nicotine stimulation promoted recruitment of PIKfyve-EGFP onto secretory vesicles in PC12 cells. YM-201636, a selective inhibitor of PIKfyve activity, and PIKfyve knockdown by small interfering RNA potentiated secretory granule exocytosis. Overexpression of PIKfyve or its yeast orthologue Fab1p inhibited regulated secretion in PC12 cells, whereas a catalytically inactive PIKfyve mutant had no effect. These results demonstrate a novel inhibitory role for PIKfyve catalytic activity in regulated secretion and provide further evidence for a fine tuning of exocytosis by 3-phosphorylated phosphoinositides.</description><subject>Animals</subject><subject>Cattle</subject><subject>Chromaffin Cells - physiology</subject><subject>Exocytosis - physiology</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Mice</subject><subject>Neurosecretory Systems - drug effects</subject><subject>Neurosecretory Systems - physiology</subject><subject>PC12 Cells</subject><subject>Phosphatidylinositol 3-Kinases - genetics</subject><subject>Phosphatidylinositol 3-Kinases - physiology</subject><subject>Phosphoinositide-3 Kinase Inhibitors</subject><subject>Rats</subject><subject>Recombinant Proteins - genetics</subject><subject>Recombinant Proteins - pharmacology</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - genetics</subject><subject>Transfection</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kEtr3DAURkVoSCZpt122povsPL2SZUtelTDkRV6lbaA7IUvXMwqeUSrZk_rfR8EDWUULCcS5H989hHymMKcg-PfHxsxvBXBZVgxgj8woyCIvSvr3A5kBMJrXrJSH5CjGR0iH1_SAHFIJRV1VYkZ-_Ly6bsctZne41L3bYjdmv3A5dLrHmJ3992bsfXQxc5uEDMFHNAF7H8ZsgV0XP5L9VncRP-3eY_JwfvZncZnf3F9cLU5vcsMr3ue1EchFY9oKaSUEF7bmltpGawRdg6jKVtvCNqh5awpk0vKW2orz9MWANcUxOZlyn4L_N2Ds1dpFkxroDfohKgZSCgo0gfMJNKlrDNiqp-DWOoyKgnpVppIy9aYsDXzZJQ_NGu0bvnOUgG8TsHLL1bMLqBrnzQrXislClekGnqCvE9Rqr_QyuKgefrPUB0CWkFZOhJwITJq2DoOKxuHGoE2RplfWu_cqvgDyNo-Y</recordid><startdate>20080201</startdate><enddate>20080201</enddate><creator>Osborne, Shona L.</creator><creator>Wen, Peter J.</creator><creator>Boucheron, Christine</creator><creator>Nguyen, Hao N.</creator><creator>Hayakawa, Masahiko</creator><creator>Kaizawa, Hiroyuki</creator><creator>Parker, Peter J.</creator><creator>Vitale, Nicolas</creator><creator>Meunier, Frederic A.</creator><general>Elsevier Inc</general><general>American Society for Biochemistry and Molecular Biology</general><scope>6I.</scope><scope>AAFTH</scope><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>7TM</scope><scope>M7N</scope></search><sort><creationdate>20080201</creationdate><title>PIKfyve Negatively Regulates Exocytosis in Neurosecretory Cells</title><author>Osborne, Shona L. ; 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Two phosphoinositides, phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3-phosphate, are important for the ATP-dependent priming of the secretory apparatus prior to Ca2+-dependent exocytosis. Mechanisms that control phosphoinositide levels are likely to play an important role in priming fine tuning. Here we have investigated the involvement of PIKfyve, a phosphoinositide 5-kinase that can phosphorylate phosphatidylinositol 3-phosphate to produce phosphatidylinositol 3,5-bisphosphate on large dense core vesicle exocytosis from neuroendocrine cells. PIKfyve localizes to a subpopulation of secretory granules in chromaffin and PC12 cells. Nicotine stimulation promoted recruitment of PIKfyve-EGFP onto secretory vesicles in PC12 cells. YM-201636, a selective inhibitor of PIKfyve activity, and PIKfyve knockdown by small interfering RNA potentiated secretory granule exocytosis. Overexpression of PIKfyve or its yeast orthologue Fab1p inhibited regulated secretion in PC12 cells, whereas a catalytically inactive PIKfyve mutant had no effect. These results demonstrate a novel inhibitory role for PIKfyve catalytic activity in regulated secretion and provide further evidence for a fine tuning of exocytosis by 3-phosphorylated phosphoinositides.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>18039667</pmid><doi>10.1074/jbc.M704856200</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cattle Chromaffin Cells - physiology Exocytosis - physiology Humans In Vitro Techniques Mice Neurosecretory Systems - drug effects Neurosecretory Systems - physiology PC12 Cells Phosphatidylinositol 3-Kinases - genetics Phosphatidylinositol 3-Kinases - physiology Phosphoinositide-3 Kinase Inhibitors Rats Recombinant Proteins - genetics Recombinant Proteins - pharmacology RNA Interference RNA, Small Interfering - genetics Transfection |
title | PIKfyve Negatively Regulates Exocytosis in Neurosecretory Cells |
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