Genetic mutations in the Kir6.2 subunit of KATP channels which cause CHI
The role of KATP channels have been best characterized in the pancreas where they are crucial for the regulation of insulin secretion from pancreatic ?-cells. In the open state, KATP channels maintain the ?-cell membrane resting potential inhibiting insulin secretion. In response to elevated glucose levels KATP channels close mediating membrane depolarization, opening of voltage-gated Ca 2+ channels, and subsequent insulin secretion. KATP channel current is controlled both by the metabolic regulation of the channel mediated via changes in the [ATP/ADP] ratio and the cell surface density of channels. Using functional and cell biological approaches the current study identifies three trafficking motifs in the Kir6.2 subunit controlling the surface density of KATP channels each with an
associated genetic disorder. The first, a di-acidic motif (280DXE282) was found to mediate efficient export of the channels from the endoplasmic reticulum. A mutation in this motif,(E282K), which causes congenital hyperinsulinism, inhibited this export thereby reducing surface channel density. The second, a tyrosine-based motif (330YSKF333) was found to be necessary for clathrin-mediated internalization of the surface expressed channels.
Disruption of this motif through mutations (Y330C & F3331)causing permanent neonatal diabetes mellitus inhibited internalization, enhancing surface channel density. Finally, an acidic di-leucine motif (352DRSLL356) was found to regulate rapid recycling of internalized
KATP channels. Disruption of this motif through a non-insulin dependent diabetes mellitus causing mutation (L355P) enhanced recycling and channel surface expression.
In summary, the current study identified motifs that control biosynthetic and endocytotic trafficking pathways and thereby the cell surf?ce expression of pancreatic KATP
channels. More importantly, the study reports that genetic mutations can disrupt each of these motifs and alter the channel cell surface density, thereby causing disease. Mutations that prevent biosynthetic export cause congenital hyperinsulinism whereas mutations that inhibit internalisation or enhance recycling cause diabetes mellitus. The study thus provides a link between genetic mutations, trafficking defects and disorders of insulin secretion.