ATP Modulation of ATP-sensitive Potassium Channel ATP Sensitivity Varies with the Type of SUR Subunit

Abstract

ATP-sensitive potassium (K ATP) ATP-sensitive potassium (K ATP )1 channels are widely distributed, being found in pancreatic B-cells, cardiac, smooth, and skeletal muscles, and neurones (1). They play important functional roles in all these tissues by linking cellular metabolism to electrical activity. Opening of the K ATP channel produces a voltage-independent K ϩ current that hyperpolarizes the cell and reduces its electrical excitability; conversely, K ATP channel closure usually decreases membrane excitability.The K ATP channel is an octamer, formed by the physical association of four inwardly rectifying potassium channel subunits (Kir6.2) and four regulatory sulfonylurea receptor subunits (2). K ATP channels in different tissues are composed of different Kir and SUR subunits. In most tissues, Kir6.2 acts as the pore-forming subunit (3, 4). Two different sulfonylurea receptor genes (SUR1 and SUR2) have been identified, and further diversity is created by alternative splicing of SUR2 (5-9). In this paper, the major isoform of SUR2 (6) is called SUR2A. It shares 67% sequence identity with SUR1. There is evidence that SUR1 serves as the regulatory subunit of the K ATP channel in pancreatic B-cells and some types of neurone (5, 10), whereas a similar role is played by SUR2A in cardiac and skeletal muscle (6).Binding sites for drugs and modulatory agents are found on both Kir6.2 and SUR subunits. The nucleotides ATP and ADP bind to an intracellular site on Kir6.2 and bring about K ATP channel closure (11, 12), whereas a range of magnesium nucleotides (including ATP and ADP) interact with the NBDs of SUR and thereby increase channel activity (13-16). The balance between these inhibitory and stimulatory effects results in channel inhibition by most concentrations of MgATP and high concentrations of MgADP (10 mM) and in channel activation by low micromolar concentrations of MgADP. It is thought that metabolic regulation of K ATP channel activity is mediated, in part, by changes in the intracellular concentrations of these nucleotides.Recent studies indicate that membrane phospholipids also play an important role in modulating K ATP channel activity. Thus, phosphatidylinositol 4,5-bisphosphate (PIP 2 ) increases the activity and reduces the ATP sensitivity of both native and cloned K ATP channels (17-21). Overexpression of PI5-kinase, which enhances PIP 2 levels, reduces the ATP sensitivity of the channel in membrane patches (21), whereas breakdown of PIP 2 by phospholipase C enhances the K ATP channel ATP sensitivity (22). This is in agreement with data indicating that PIP 2 binds directly to Kir channels (23). Interestingly, application of PIP 3 and PI 3-P also enhances K ATP channel activity (19,20,24).The rundown of both native and cloned K ATP channels that occurs in excised membrane patches is reversed by application of MgATP (25-27), and PIP 2 has also been implicated in this effect (25). It is postulated that PIP 2 is produced in plasma membrane by serial phosphorylation of PI and that this process is sequent...

Hybrid assemblies of ATP-sensitive K + channels determine their muscle-type-dependent biophysical and pharmacological properties

“…Furthermore, muscles showing a high current density such as FDB and TA were also highly responsive to drugs, indicating that the drug efficacy and drug specificity depend on the drug binding sites available and the type of subunit expressed. Fourth, our observation that the IC 50 for ATP of the FDB channels was significantly lower than that of TA, EDL, and SOL channels is in line with the fact that the channels composed of SUR1 are more sensitive to ATP inhibition than channels composed of SUR2A and -B subunits (16).…”

PTH-induced internalization of apical membrane NaPi2a: role of actin and myosin VI

“…Actin has shown to be involved in the trafficking of several transporters and channels including aquaporin-2 (28), the sodium-hydrogen exchanger (13), and the ATP-sensitive potassium channel (33). In addition, a dynamic actin cytoskeleton has been shown to be necessary for myosin-based transport within cells (32).…”

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

“…The sulfonylurea receptor is a regulatory subunit because it: 1) confers sensitivity to Mg-nucleotides, 2) is activated by K 1 channel openers such as diazoxide and pinacidil, and 3) is inhibited by sulfonylureas such as glibenclamide and tolbutamide (Aguilar-Bryan and Bryan, 1999). In addition, SUR1 increases the open probability of Kir6.2 via phosphatidylinositol-4, 5-biphosphate (PIP2) (Song and Ashcroft, 2001) and may increase the sensitivity to ATP .…”