The pancreatic beta-cell isoform of KATP channels, consisting of SURI and KIR6.2 subunits, plays a key role in coupling glucose metabolism to membrane electrical activity. Mutations in either subunit can cause a recessive form of neonatal hypoglycemia termed persistent hyperinsulinemic hypoglycemia of infancy, or PHHI. Recent work has shown that both subunits have trafficking signals. SURI and KIR6.2 have endoplasmic reticulum (ER) retention signals, while we have established that the C-terminus of SURI has an additional signal, which is required for surface expression even in the absence of the ER retention signals. The ER retention signals are 'masked' during channel assembly, and together these two sets of signals act as a quality control mechanism to insure that only completely assembled channels, (SUR1/KIR6.2)4, with both nucleotide-binding folds intact reach the cell surface. A number of PHHI mutations truncate SURI; it is proposed that these deletions remove the C-terminal signal and that the SURIAC channels then fail to reach the cell surface, which accounts for the observed loss of channel activity. The nature of these recently discovered trafficking signals, how they function, and what proteins they interact with is not understood. The objective of this application is to study the role of membrane trafficking in the correct surface expression of KATP channels by determining how the SURI C-terminal 'anterograde' signal works, specifically the investigators propose to: 1. Determine if removal of the SURI C-terminal signal results in increased rates of degradation or targeting to different degradation pathways. 2. Identify """"""""receptor(s)"""""""" that may mediate the activity of the SURI carboxyl terminus. 3. Examine the behavior of SURI missense mutations that we have shown exhibit trafficking defects. 4. Characterize the order of assembly of KATP channel sub-units.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK057671-02
Application #
6498184
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
2001-02-15
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$321,694
Indirect Cost
Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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