NDLI: Functional analysis of six Kir6.2 (KCNJ11) mutations causing neonatal diabetes

Content Provider	Springer Nature Link
Author	Girard, Christophe A. J. Shimomura, Kenju Proks, Peter Absalom, Nathan Casta, Luis de Nanclares, Guiomar Ashcroft, Frances M.
Copyright Year	2006
Abstract	ATP-sensitive potassium (KATP) channels, composed of pore-forming Kir6.2 and regulatory sulphonylurea receptor (SUR) subunits, play an essential role in insulin secretion from pancreatic beta cells. Binding of ATP to Kir6.2 inhibits, whereas interaction of Mg-nucleotides with SUR, activates the channel. Heterozygous activating mutations in Kir6.2 (KCNJ11) are a common cause of neonatal diabetes (ND). We assessed the functional effects of six novel Kir6.2 mutations associated with ND: H46Y, N48D, E227K, E229K, E292G, and V252A. KATP channels were expressed in Xenopus oocytes and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of SUR). All mutations reduced the sensitivity of the KATP channel to inhibition by MgATP, and enhanced whole-cell KATP currents. Two mutations (E227K, E229K) also enhanced the intrinsic open probability of the channel, thereby indirectly reducing the channel ATP sensitivity. The other four mutations lie close to the predicted ATP-binding site and thus may affect ATP binding. In pancreatic beta cells, an increase in the KATP current is expected to reduce insulin secretion and thereby cause diabetes. None of the mutations substantially affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting patients carrying these mutations may respond to these drugs.
Starting Page	323
Ending Page	332
Page Count	10
File Format	PDF
ISSN	00316768
Journal	Pflügers Archiv
Volume Number	453
Issue Number	3
e-ISSN	14322013
Language	English
Publisher	Springer-Verlag
Publisher Date	2006-09-22
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	ATP-sensitive potassium channel Neonatal diabetes Kir6.2 Insulin secretion Sulphonylureas SUR1 Human Physiology
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Clinical Biochemistry

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