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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Role of ubiquitin-proteasome degradation pathway in biogenesis efficiency of -cell ATP-sensitive potassium channels

Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon

Submitted 18 May 2005 ; accepted in final form 24 June 2005

ABSTRACT

ATP-sensitive potassium (K_ATP) channels of pancreatic -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 -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 -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 -cell K_ATP channels.

endoplasmic reticulum-associated degradation; sulfonylurea receptor-1; Kir6.2; proteasome inhibitors

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