Biochemistry and physiology of the ATP-sensitive potassium channel

ATP-sensitive potassium (K _ATP) channels are present in the surface membranes of many organs and cell types. In the pancreatic beta-cell, they play a critical role in coupling glucose metabolism to insulin secretion, and over the last few years, significant advances have been made in understanding the molecular basis of K _ATP channel activity, as well as the role of these channels in physiology and disease. K _ATP channels are generated from coassembly of Kir6.2 pore-forming subunits with sulfonylurea receptor 1 (SUR1) regulatory subunits. They are inhibited by intracellular ATP, and activated by ADP, so that glucose oxidation in beta-cells leads to a rise in [ATP]:[ADP] ratio, which reduces K _ATP channel activity and causes membrane depolarization. This leads to the opening of voltage dependent Ca ²⁺ channels, elevated intracellular [Ca ²⁺], and insulin exocytosis. Sulfonylureas, hypoglycemic agents used in the treatment of type 2 diabetes, act by binding to the regulatory SUR1 subunit and directly inhibiting the K _ATP current, bypassing metabolism to trigger insulin secretion. Conversely, K _ATP-specific channel openers (diazoxide) suppress insulin release by activating K _ATP and preventing a depolarization-dependent rise in intracellular [Ca ²⁺]. Loss-of-function mutations in the genes (KCNJ11, ABCC8) that encode the two subunits (Kir6.2 and SUR1, respectively) of the K _ATP channel underlie hyperinsulinism that can in some cases be treated by potassium channel openers. This chapter will focus on advances in K _ATP channel biochemistry and physiology, and consider implications for future understanding of the mechanisms of control of insulin secretion in normal and diseased states.