Am J Physiol Cell Physiol AJP: Endocrinology and Metabolism
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Am J Physiol Cell Physiol (June 29, 2005). doi:10.1152/ajpcell.00240.2005
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Submitted on May 18, 2005
Accepted on June 24, 2005

A ROLE OF THE UBIQUITIN-PROTEASOME DEGRADATION PATHWAY IN THE BIOGENESIS EFFICIENCY OF {beta}-CELL ATP-SENSITIVE POTASSIUM CHANNELS

Fei-Fei Yan1, Chia-Wei Lin1, Etienne A Cartier1, and Show-Ling Shyng1*

1 Center for Research on Occupational & Environmental Toxicology, Oregon Health & Science University, Portland, OR, USA

* To whom correspondence should be addressed. E-mail: shyngs{at}ohsu.edu.

ATP-sensitive potassium (KATP) channels of pancreatic {beta}-cells mediate glucose-induced insulin secretion by linking glucose metabolism to membrane excitability. The number of plasma membrane KATP channels determines the sensitivity of {beta}-cells to glucose stimulation. The KATP channel is formed in the endoplasmic reticulum (ER) upon co-assembly 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 biogenesis efficiency and expression of the channel. 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 KATP channels. We provide evidence that, when expressed in COS cells, both Kir6.2 and SUR1 undergo ER-associated degradation (ERAD) via the ubiquitin-proteasome system. Moreover, treatment of cells with proteasome inhibitors MG132 or lactacystin leads to increased surface expression of KATP channels by increasing the efficiency of channel biogenesis. Importantly, inhibition of proteasome function in a pancreatic {beta}-cell line, INS-1, that express endogenous KATP 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 KATP channels.




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