title: Endoplasmic reticulum accumulation of Kir6.2 without activation of ER stress response in islet cells from adult Sur1 knockout mice.
abstract: Trafficking of pancreatic K(ATP) channels to the plasma membrane critically depends on masking the endoplasmic reticulum (ER) retention signals of the SUR1 and Kir6.2 subunits upon their proper assembly into functional hetero-octamers. When expressed in the absence of the partner protein, each subunit might accumulate in the ER and trigger beta-cell ER stress and oxidative stress. To test this hypothesis, Kir6.2 localisation, ER ultra-structure and ER-stress- and oxidative-stress-response gene mRNA levels were evaluated in pancreatic endocrine cells from adult wild-type (WT) and Sur1 knockout (Sur1 ( -/- )) mice. As previously reported, Kir6.2 was mainly expressed on secretory granules and at the plasma membrane of WT islet cells. In contrast, like the ER chaperone calreticulin, Kir6.2 was primarily localised in the rough endoplasmic reticulum (RER) of Sur1 ( -/- ) islet cells. ER retention of Kir6.2 was demonstrated (electron microscopy) by a significant increase in the length and Kir6.2 density of RER in Sur1 ( -/- ) vs WT islet cells. Despite Kir6.2 retention in RER, Xbp1 mRNA splicing and mRNA levels of preproinsulin and ER-stress-response genes Bip, Edem and Gadd153 were similar in WT and Sur1 ( -/- ) islets. However, mRNA levels of the antioxidant enzymes Sod1, Sod2, Gpx2 and catalase were significantly up-regulated in Sur1 ( -/- ) islets. Sequestration of Kir6.2 in RER of Sur1 ( -/- ) islet cells is thus associated with an increase in RER length and mild oxidative stress without activation of the classical ER stress response.
authors.affiliation: Department of Pathology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Tour Rosalind Franklin, 10 Avenue Hippocrate, 1200, Brussels, Belgium.
authors.forename: Ihsane
authors.initials: I
authors.lastname: Marhfour
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Jonas
authors.forename: Joëlle
authors.initials: J
authors.lastname: Marchandise
authors.forename: Alberte
authors.initials: A
authors.lastname: Lefevre
authors.forename: Jacques
authors.initials: J
authors.lastname: Rahier
authors.forename: Christine
authors.initials: C
authors.lastname: Sempoux
authors.forename: Yves
authors.initials: Y
authors.lastname: Guiot
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D037282:Calreticulin / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000235:genetics; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011955:Receptors, Drug / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D013347:Subcellular Fractions / Q000378:metabolism; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D037282:Calreticulin; D024661:Potassium Channels, Inwardly Rectifying; D012333:RNA, Messenger; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577508:Abcc8 protein, mouse