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Click to add/remove this article to your list of 'My Favorites' Analysis of KATP Channel Defects Caused by Sulfonylurea Receptor 1 Mutations Associated with Congenital Hyperinsulinism

Year: 2005

Abstract Number: 177-OR


Institutions: Portland, OR; Philadelphia, PA

Results: Pancreatic β-cell ATP-sensitive potassium (KATP) channels, formed by sulfonylurea receptor 1 (SUR1) and Kir6.2, regulate insulin secretion by coupling cell metabolism to membrane excitability. Mutation in the channel genes that leads to loss of channel function is the major cause of congenital hyperinsulinism (CHI). Here, we analyzed the effects of twenty SUR1 mutations identified in CHI on cell surface expression and functional properties of KATP channels. Of the twenty mutations, many caused a severe reduction in the level of channel expression at the cell surface, indicating an effect on channel biogenesis or trafficking, while some caused reduced channel response to the physiological stimulator MgADP. In general, there is good correlation between our in vitro functional data and the clinical phenotypes observed in patients. Treatment of cells with sulfonylurea drugs such as glibenclamide or tolbutamide significantly improved surface expression of some mutants, including G7R, N24K, F27S, R74W, and E128K. Inactivation of the ER retention/retrieval signal RKR in SUR1 by mutation to AAA also significantly improved surface expression of a subset of the biogenesis/trafficking mutants, including G7R, N24K, F27S, and L1350Q. Interestingly, all mutations that responded to sulfonylurea treatment are located in the first transmembrane domain (known as TM0) of SUR1. By contrast, mutations that responded to the RKR to AAA genetic manipulation are not only found in TM0 but also in the C-terminal domain of SUR1. All biogenesis/trafficking mutants whose surface expression could be improved by genetic or pharmacological manipulations retain full or partial response to the physiological stimulator MgADP and the KATP channel opener diazoxide. Our studies expand the list of CHI-causing SUR1 mutations whose adverse effects on the functional expression of KATP channels may be corrected by genetic or pharmacological manipulations.