ATP-sensitive potassium (KATP) channels are present in the surface membranes of many organs and cell types. Over the last two decades, significant advances have been made in understanding the molecular basis of KATP channel activity, as well as their role in physiology and pathophysiology. KATP channels are heterooctameric complexes of coassembly of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits (encoded by KCNJ11 and ABCC8 genes, respectively). KATP channels are regulated by adenosine nucleotides, are inhibited by intracellular ATP, and activated by ADP. In the pancreatic ?-cell, KATP channels play a critical role in coupling glucose metabolism to insulin secretion. Normally, glucose oxidation leads to a rise in [ATP]:[ADP] ratio, which reduces KATP channel activity and causes membrane depolarization. This leads to subsequent opening of voltage-dependent Ca2+ channels, and increase in intracellular [Ca2+], which in turn promotes insulin vesicles to fuse to the plasma membrane and release insulin. Sulfonylureas (SUs), oral hypoglycemic agents widely used in the treatment of diabetes, act by binding to the SUR1 subunit thus inhibiting KATP current and inducing insulin secretion, independently of the metabolic state of the cell. Conversely, KATP-specific channel openers (ie, diazoxide) suppress insulin release by activating KATP and preventing depolarization-dependent rise in intracellular [Ca2+]. Loss-of-function mutations in the KCNJ11 and ABCC8 genes of the KATP channel underlie hyperinsulinism that can in some cases be treated by potassium channel openers. Conversely, gain-of-function mutations are the main cause of human neonatal diabetes mellitus which can now be treated by SUs, and a common KATP variant (E23K) is highly associated as a risk factor for development of type-2 diabetes. This chapter will focus on advances in KATP channel biochemistry and physiology, as well as on the mechanistic basis by which KATP mutations underlie these insulin secretory disorders.
|Title of host publication||Ion Channels in Health and Disease|
|Number of pages||23|
|State||Published - Jul 29 2016|