Premium
Kir6.2 mutations causing neonatal diabetes prevent endocytosis of ATP‐sensitive potassium channels
Author(s) -
Mankouri Jamel,
Taneja Tarvinder K,
Smith Andrew J,
Ponnambalam Sreenivasan,
Sivaprasadarao Asipu
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601275
Subject(s) - biology , kir6.2 , endocytosis , potassium channel , sulfonylurea receptor , microbiology and biotechnology , adenosine triphosphate , atp sensitive potassium channel , mutation , genetics , diabetes mellitus , biochemistry , protein subunit , biophysics , gene , endocrinology , receptor , glibenclamide
ATP‐sensitive potassium (K ATP ) channels couple the metabolic status of a cell to its membrane potential—a property that endows pancreatic β‐cells with the ability to regulate insulin secretion in accordance with changes in blood glucose. The channel comprises four subunits each of Kir6.2 and the sulphonylurea receptor (SUR1). Here, we report that K ATP channels undergo rapid internalisation from the plasma membrane by clathrin‐mediated endocytosis. We present several lines of evidence to demonstrate that endocytosis is mediated by a tyrosine based signal ( 330 YSKF 333 ) located in the carboxy‐terminus of Kir6.2 and that SUR1 has no direct role. We show that genetic mutations, Y330C and F333I, which cause permanent neonatal diabetes mellitus, disrupt this motif and abrogate endocytosis of reconstituted mutant channels. The resultant increase in the surface density of K ATP channels would predispose β‐cells to hyperpolarise and may account for reduced insulin secretion in these patients. The data imply that endocytosis of K ATP channels plays a crucial role in the (patho)‐physiology of insulin secretion.