title: Syntaxin 1A regulates surface expression of beta-cell ATP-sensitive potassium channels.
abstract: The pancreatic ATP-sensitive potassium (K(ATP)) channel consisting of four inwardly rectifying potassium channel 6.2 (Kir6.2) and four sulfonylurea receptor SUR1 subunits plays a key role in insulin secretion by linking glucose metabolism to membrane excitability. Syntaxin 1A (Syn-1A) is a plasma membrane protein important for membrane fusion during exocytosis of insulin granules. Here, we show that Syn-1A and K(ATP) channels endogenously expressed in the insulin-secreting cell INS-1 interact. Upregulation of Syn-1A by overexpression in INS-1 leads to a decrease, whereas downregulation of Syn-1A by small interfering RNA (siRNA) leads to an increase, in surface expression of K(ATP) channels. Using COSm6 cells as a heterologous expression system for mechanistic investigation, we found that Syn-1A interacts with SUR1 but not Kir6.2. Furthermore, Syn-1A decreases surface expression of K(ATP) channels via two mechanisms. One mechanism involves accelerated endocytosis of surface channels. The other involves decreased biogenesis and processing of channels in the early secretory pathway. This regulation is K(ATP) channel specific as Syn-1A has no effect on another inward rectifier potassium channel Kir3.1/3.4. Our results demonstrate that in addition to a previously documented role in modulating K(ATP) channel gating, Syn-1A also regulates K(ATP) channel expression in β-cells. We propose that physiological or pathological changes in Syn-1A expression may modulate insulin secretion by altering glucose-secretion coupling via changes in K(ATP) channel expression.
authors.affiliation: Dept. of Biochemistry and Molecular Biology, School of Medicine, Oregon Health & Science Univ., 3181 S. W. Sam Jackson Park Rd., Portland, OR 97239, USA.
authors.forename: Pei-Chun
authors.initials: PC
authors.lastname: Chen
authors.forename: Cathrin E
authors.initials: CE
authors.lastname: Bruederle
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Gaisano
authors.forename: Show-Ling
authors.initials: SL
authors.lastname: Shyng
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D015536:Down-Regulation / Q000235:genetics; D004705:Endocytosis / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D054086:KATP Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D034622:RNA Interference / Q000502:physiology; D051381:Rats; D011955:Receptors, Drug / Q000378:metabolism; D064233:Sulfonylurea Receptors; D050827:Syntaxin 1 / Q000096:biosynthesis / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; C577509:Abcc8 protein, rat; D007328:Insulin; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D050827:Syntaxin 1; D005947:Glucose