Differential roles for SUR subunits in KATP channel membrane targeting and regulation.

SINCE THEIR DISCOVERY OVER 25 years ago, ATP-sensitive K (KATP) channels have been studied extensively in many tissues, including heart, pancreas, brain, skeletal and smooth muscle, pituitary, and kidney (6, 10, 18, 19). KATP channels are critical sensors that couple cellular metabolic state to membrane excitability and organ function and regulate a wide range of cellular functions including hormone secretion, vascular tone, cardiomyocyte contractility, and synaptic transmission (6, 18, 19). In heart, the activation of KATP channels during ischemia shortens action potential duration to help preserve energy in the face of a decreased supply (6, 10). In pancreatic -cells, KATP channels couple membrane potential (and therefore insulin release) to a metabolic state and are the target of the sulfonylurea class of antidiabetic drugs (6, 10). In vascular smooth muscle, KATP channels regulate basal tone and promote vasodilation in response to severe hypoxia. Importantly, variants in KATP channel genes have been linked to human disease, including congenital hyperinsulinemia, neonatal diabetes, and atrial and ventricular arrhythmias (2, 18, 19). Despite the importance of KATP channels in many critical cellular functions and their clinical importance as drug targets, little is known about the cellular pathways that regulate the membrane expression of these critical channels. In this issue of the American Journal of Physiology-Heart and Circulatory Physiology, Bao and colleagues (1) add to our understanding of this critical channel by studying the roles for KATP channel sulfonylurea receptor (SUR) subunits in differential localization of KATP channels in submembrane compartments. The KATP channel is a hetero-octameric complex comprised of four pore-forming inward rectifier K channels subunits (Kir6.1 or Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and four regulatory SUR subunits (SUR1, SUR2A/ SUR2B, encoded by ABCC8 and ABCC9, respectively). Kir6.1 and Kir6.2 are comprised of a cytoplasmic NH2-terminus, two transmembrane domains (M1 and M2) with high homology to pore-forming S5–S6 segments of voltage-gated K channels, and a cytoplasmic COOH-terminus (10, 18). Whereas Kir6.1 is the dominant pore-forming subunit found in KATP channels from vascular smooth muscle, Kir6.2 is important in pancreatic -cell, cardiac myocyte, and nonvascular smooth muscle KATP channels (19). Thus Kir6.1 plays important roles in regulating vascular tone, whereas Kir6.2 is critical for glucose homeostasis and ischemic preconditioning (19). SUR subunits are members of the ATP-binding cassette (ABC) membrane protein family. These subunits contain an NH2-terminal transmembrane domain (TM0) and cytoplasmic linker (L0) that interact with Kir6, two additional transmembrane domains (although no transport function has been identified for SUR), and two cytoplasmic nucleotide-binding folds (NBF1 and NBF2) that contain binding sites for Mg -adenosine nucleotides. While Kir6.2 and SUR2 (SUR2A in particular) are predominantly expressed in heart, Kir6.1 and SUR1 are also found in heart. While knockout mice have generated important insight into the role of different subunits in heart, the story is far from complete. Kir6.2 / mice have virtually no cardiac KATP channel activity consistent with Kir6.2 being the dominant pore-forming subunit in heart (24). Isolated ventricular myocytes from Kir6.2 / mice show normal action potential duration and contractility at baseline but diminished ischemic cardioprotection similar to the effect of KATP channel blockers (24, 25, 29). Ventricular myocytes from SUR2 / mice show a dramatic loss of KATP channel activity; however, SUR2 / animals are protected from global ischemia likely because of the effects in other tissues (23). Interestingly, data from SUR1 / mice show normal ventricular KATP currents but a loss of atrial KATP current (7), suggesting that within the heart there is a heterogeneous KATP channel subunit composition. A hallmark property of the KATP channel is its regulation by intracellular nucleotides. In response to a decrease in the ATP-to-ADP ratio, KATP channels activate, leading to K efflux from the cell, membrane hyperpolarization, and suppression of electrical activity. At the molecular level, ATP (in the absence of Mg ) inhibits the channel by binding directly to Kir6 in a binding pocket located at the interface of the NH2and COOH-termini to inhibit the channel. Thus the channel stoichiometry provides each KATP channel with four ATP binding sites. Several mutations in Kir6.2 linked to neonatal diabetes alter ATP sensitivity and/or channel gating (9, 13, 14, 16, 28). In contrast, Mg -ADP and Mg -ATP both activate the channel by binding to SUR, which effectively decreases the IC50 of ATP binding to Kir6. Most KATP channel mutations linked with congenital hyperinsulinemia reside in SUR1 and reduce Mg -ADP activation, resulting in a loss of channel function (18). In addition to intracellular nucleotides, KATP channel activity is regulated by a wide range of factors including phospholipids [e.g., phosphatidylinositol 4,5-bisphosphate (PIP2)], acyl-CoA, pH, pharmacological agents, the cytoskeleton, and phosphorylation (e.g., by PKA and PKC) (3, 8, 26). For example, PIP2 binding to Kir6.2 activates the KATP channel, whereas PIP2 hydrolysis via phospholipase C inhibits the channel (5, 11). KATP channels reside within dynamic macromolecular complexes comprised of kinases, cytoskeletal and adapter proteins in addition to Kir6 and SUR subunits (6, 10). Enzymes (i.e., creatine kinase, adenylate kinase, and lactate dehydrogenase) are integral components of this complex and regulate channel function (21). Syntaxin 1A, a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein inAddress for reprint requests and other correspondence: P. J. Mohler, Dept. of Internal Medicine, Univ. of Iowa Carver College of Medicine, 285 Newton Rd., CBRB 2283, Iowa City, IA, 52242 (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 300: H33–H35, 2011; doi:10.1152/ajpheart.01088.2010. Editorial Focus