Physiological Roles of K
The physiological importance of KATP channels in insulin secretion was established >20 years ago. At substimulatory glucose concentrations, K+ efflux through open KATP channels maintains the β-cell membrane at a hyperpolarized potential of around -70 mV, which keeps voltage-gated Ca2+ channels closed. Elevation of the blood glucose concentration increases glucose uptake and metabolism by the β-cell, producing changes in cytosolic nucleotide concentrations that cause KATP channel closure. This leads to a membrane depolarization that opens voltage-gated Ca2+ channels initiating β-cell electrical activity and Ca2+ influx, and the subsequent rise in [Ca2+]i triggers exocytosis of insulin granules. Although glucose has additional (downstream) effects on insulin secretion, under physiological conditions KATP channel closure is a central step in glucose-stimulated insulin release. KATP channels are also the target for sulfonylurea drugs, which are widely used to treat type 2 diabetes. These drugs stimulate insulin secretion by binding to, and closing, KATP channels. Thus, sulfonylureas bypass β-cell metabolism but subsequently stimulate the same chain of events as glucose.
In addition to their well-characterized role in insulin secretion,[5,8] KATP channels have many other functions (rev. in ). They contribute to glucose homeostasis by controlling glucagon-like peptide 1 secretion from L-cells and glucose uptake in skeletal muscle, and they mediate the counter-regulatory response to glucose via effects on hypothalamic neurons. They are also involved in the response to cardiac stress and ischemic preconditioning,[13,14] regulate vascular smooth muscle tone, modulate electrical activity and transmitter release at brain synapses,[16,17] and protect against seizures.[18,19] In all these tissues, KATP channels couple metabolism to electrical activity. Increased metabolism produces channel closure, membrane depolarization, and electrical activity, and conversely, metabolic inhibition opens KATP channels and suppresses electrical activity. In glucose-sensing tissues, KATP channels respond to changes in blood glucose concentration, but in many other tissues they open only under ischemic conditions or in response to hormonal stimulation.
KATP channels are subject to complex regulation by numerous cytosolic factors, the most important being the adenine nucleotides ATP and magnesium ADP (MgADP). Under physiological conditions, channel activity is determined by the balance between ATP, which blocks the channel, and MgADP, which reverses channel inhibition by ATP.[8,9,20] Consequently, reciprocal changes in the intracellular concentrations of ATP and MgADP probably mediate the metabolic regulation of the KATP channel.
The KATP channel is a 4:4 complex of Kir6.x and sulfonylurea receptor (SUR) subunits.[9,21] In most tissues, the pore-forming subunit is Kir6.2; binding of ATP to Kir6.2 results in channel closure. SUR acts as a regulatory subunit, conferring stimulation by Mg nucleotides and K-channel openers (such as diazoxide) and inhibition by sulfonylureas.[22,23] Like the Kir subunit, SUR exists in more than one isoform, and variation in SUR subunit composition accounts for the different metabolic and drug sensitivities of KATP channels.[7,9] SUR1 is found in pancreas and brain muscle, SUR2A in heart and skeletal muscle, and SUR2B in brain and smooth muscle.
Studies on genetically modified mice have provided valuable insights into the role of the KATP channel in β-cells. These have shown that targeted overactivity of β-cell KATP channels induces profound neonatal diabetes, whereas targeted suppression of KATP channel activity leads to hyperinsulinism. Complete knockout of Kir6.2 or SUR1 causes hyperinsulinism in neonates, but hypoinsulinism occurs in adult animals due to apoptotic loss of β-cell mass.[9,26]
Further support for the importance of KATP channels in insulin secretion comes from the fact that naturally occurring loss-of-function mutations in either the human SUR1 or Kir6.2 (KCNJ11) genes are the most common causes of congenital hyperinsulinism of infancy (CHI). Some CHI mutations not only cause neonatal hyperinsulinism but also result in β-cell dysfunction and diabetes in adult life.
Diabetes. 2005;54(9):2503-2513. © 2005 American Diabetes Association, Inc.
Cite this: Activating Mutations in Kir6.2 and Neonatal Diabetes - Medscape - Sep 01, 2005.