title: The Rab27a effector exophilin7 promotes fusion of secretory granules that have not been docked to the plasma membrane.
abstract: Granuphilin, an effector of the small GTPase Rab27a, mediates the stable attachment (docking) of insulin granules to the plasma membrane and inhibits subsequent fusion of docked granules, possibly through interaction with a fusion-inhibitory Munc18-1/syntaxin complex. However, phenotypes of insulin exocytosis differ considerably between Rab27a- and granuphilin-deficient pancreatic β cells, suggesting that other Rab27a effectors function in those cells. We found that one of the putative Rab27a effector family proteins, exophilin7/JFC1/Slp1, is expressed in β cells; however, unlike granuphilin, exophilin7 overexpressed in the β-cell line MIN6 failed to show granule-docking or fusion-inhibitory activity. Furthermore, exophilin7 has no affinities to either Munc18-1 or Munc18-1-interacting syntaxin-1a, in contrast to granuphilin. Although β cells of exophilin7-knockout mice show no apparent abnormalities in intracellular distribution or in ordinary glucose-induced exocytosis of insulin granules, they do show impaired fusion in response to some stronger stimuli, specifically from granules that have not been docked to the plasma membrane. Exophilin7 appears to mediate the fusion of undocked granules through the affinity of its C2A domain toward the plasma membrane phospholipids. These findings indicate that the two Rab27a effectors, granuphilin and exophilin7, differentially regulate the exocytosis of either stably or minimally docked granules, respectively.
authors.affiliation: Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Ray
authors.initials: R
authors.lastname: Ishizaki
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kasai
authors.forename: Eri
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Gomi
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Izumi
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D005089:Exocytosis; D005260:Female; D015870:Gene Expression; D005947:Glucose / Q000502:physiology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D008561:Membrane Fusion; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051938:Munc18 Proteins / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D021381:Protein Transport; D022142:Secretory Vesicles / Q000378:metabolism*; D050827:Syntaxin 1 / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D007328:Insulin; D008565:Membrane Proteins; D051938:Munc18 Proteins; D010743:Phospholipids; C497938:Stxbp1 protein, mouse; D050827:Syntaxin 1; C424133:Sytl1 protein, mouse; C122015:Sytl4 protein, mouse; D033921:Vesicular Transport Proteins; D000075745:rab27 GTP-Binding Proteins; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins; D005947:Glucose