TY - CHAP
T1 - Biochemistry and physiology of the ATP-sensitive potassium channel
AU - Remedi, Maria S.
AU - Nichols, Colin G.
PY - 2012
Y1 - 2012
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84859188006&partnerID=8YFLogxK
U2 - 10.1159/000334464
DO - 10.1159/000334464
M3 - Chapter
AN - SCOPUS:84859188006
SN - 9783805599436
T3 - Frontiers in Diabetes
SP - 7
EP - 17
BT - Monogenic Hyperinsulinemic Hypoglycemia Disorders
A2 - Charles, Stanley
A2 - Diva, De Leon
ER -