The Size of a Single Residue of the Sulfonylurea Receptor Dictates the Effectiveness of K_ATP Channel Openers

Abstract

K ATP channel openers are a diverse group of molecules able to activate ATP-sensitive K ϩ channels in a tissue-dependent manner by binding to the channel regulatory subunit, the sulfonylurea receptor (SUR), an ATP-binding cassette protein. Residues crucial to this action were previously identified in the last transmembrane helix of SUR, transmembrane helix 17. This study examined the residue at the most important position, 1253 in the muscle isoform SUR2A and the matching 1290 in the pancreatic/neuronal isoform SUR1 (rat numbering). At this position in either isoform, a threonine enables action of openers, whereas a methionine prohibits it. Using single-point mutagenesis, we have examined the physicochemical basis of this phenomenon and discovered that it relied uniquely on side chain volume and not on shape, polarity, or hydrogen-bonding capacity of the residue. Moreover, the aromatic nature of neighboring residues conserved in SUR1 and SUR2A was found necessary for SUR2A to sustain the wild-type levels of channel activation by the openers tested, the cromakalim analog SR47063 [4-(2-cyanimino-1,2-dihydro-1-pyridyl)-2,2-dimethyl-6-nitrochromene] and the pinacidil analog P1075 [N-cyano-NЈ-(1,1-dimethylpropyl)-NЈ-3-pyridylguanidine]. These observations suggest that these residues can interact with openers via nonspecific stacking interactions provided that the adjacent 1253/1290 residue does not obstruct access. The smaller Thr1253 of SUR2A would permit activation, whereas the bulky Met1290 of SUR1 would not. This hypothesis is discussed in the context of a simple molecular model of transmembrane helix 17.

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

“…The binding site for cromakalim, pinacidil and nicorandil is located within the TM2 domain of SUR2. The nucleotides L1249 and T1253 in SUR2A and T1286 and M1290 in SUR2B are necessary and sufficient for the channel opener effects [61][62][63] . K ATP channels in smooth muscle respond to all of these drugs.…”

Role of ATP-Dependent Potassium Channels in Pulmonary Vascular Tone of Fetal Lambs With Congenital Diaphragmatic Hernia

“…These channels are found in different tissues, including pancreatic ␤ cells, cardiac, brain, skeletal and smooth muscle cells and are activated by a number of synthetic vasodilators such as pinacidil and are inhibited by oral hypoglycemic sulfonylurea drugs such as GLI. The mechanism of the K ATP channel opening is the result of the fixation of an opener on the channel regulatory subunit SUR, which is an ATP-binding cassette protein (37). The pulmonary vasodilator effect of pinacidil was attributed to the direct activation of K ATP channels on smooth muscle cells with a decrease of intracellular Ca 2ϩ concentration or to the activation of endothelial K ATP channels with activation of EDNO (38).…”

“…In this study, we specifically investigated K ATP channels. K ATP channel is a hetero-octameric protein of poreforming subunits, composed of inwardly rectifying K ϩ channel (K ir ) and sulfonylurea receptor (SUR) subunits (36,37). These channels are found in different tissues, including pancreatic ␤ cells, cardiac, brain, skeletal and smooth muscle cells and are activated by a number of synthetic vasodilators such as pinacidil and are inhibited by oral hypoglycemic sulfonylurea drugs such as GLI.…”

From Cromakalim to Different Structural Classes of KATP Channel Openers

“…SUR1 is found in pancreatic β-cells (Kir6.2/SUR1) [19,23], SUR2A in cardiac and skeletal muscle (Kir6.2/SUR2A) [26][27][28], and SUR2B in some neurons and in non-vascular (Kir6.2/SUR2B) [25,29], as well as in vascular (Kir6.2/SUR2B or Kir6.1/SUR2B) [30,31], smooth muscle. Evidence has accumulated indicating that the binding site/sites for most K ATP channel activators and blockers lies on the SUR subunit; this may provide a rational basis for identifying tissue-selective modulators [21,[32][33][34][35][36].…”