Role of ubiquitin-proteasome degradation pathway in biogenesis efficiency of {beta}-cell ATP-sensitive potassium channels.
ATP-sensitive potassium (K(ATP)) channels of pancreatic beta-cells mediate glucose-induced insulin secretion by linking glucose metabolism to membrane excitability. The number of plasma membrane K(ATP) channels determines the sensitivity of beta-cells to glucose stimulation. The K(ATP) channel is formed in the endoplasmic reticulum (ER) on coassembly of four inwardly rectifying potassium channel Kir6.2 subunits and four sulfonylurea receptor 1 (SUR1) subunits. Little is known about the cellular events that govern the channel's biogenesis efficiency and expression. Recent studies have implicated the ubiquitin-proteasome pathway in modulating surface expression of several ion channels. In this work, we investigated whether the ubiquitin-proteasome pathway plays a role in the biogenesis efficiency and surface expression of K(ATP) channels. We provide evidence that, when expressed in COS cells, both Kir6.2 and SUR1 undergo ER-associated degradation via the ubiquitin-proteasome system. Moreover, treatment of cells with proteasome inhibitors MG132 or lactacystin leads to increased surface expression of K(ATP) channels by increasing the efficiency of channel biogenesis. Importantly, inhibition of proteasome function in a pancreatic beta-cell line, INS-1, that express endogenous K(ATP) channels also results in increased channel number at the cell surface, as assessed by surface biotinylation and whole cell patch-clamp recordings. Our results support a role of the ubiquitin-proteasome pathway in the biogenesis efficiency and surface expression of beta-cell K(ATP) channels.
Center for Research on Occupational and Environmental Toxicology, Oregon Health and Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, USA.
Fei-Fei
FF
Yan
Chia-Wei
CW
Lin
Etienne A
EA
Cartier
Show-Ling
SL
Shyng
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D015870:Gene Expression; D007515:Islets of Langerhans / Q000378:metabolism*; D009154:Mutation; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D021381:Protein Transport; D011955:Receptors, Drug / Q000235:genetics / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D025801:Ubiquitin / Q000502:physiology*; D000099161:Kcnj11 Channel
D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D046988:Proteasome Endopeptidase Complex; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D025801:Ubiquitin; D000099161:Kcnj11 Channel