Differential Structure of Atrial and Ventricular KATP: Atrial KATP Channels Require SUR1

The isoform-specific structure of the ATP-sensitive potassium (KATP) channel endows it with differential fundamental properties, including physiological activation and pharmacology. Numerous studies have convincingly demonstrated that the pore-forming Kir6.2 (KCNJ11) and regulatory SUR2A (ABCC9) subunits are essential elements of the sarcolemmal KATP channel in cardiac ventricular myocytes. Using a novel antibody directed against the COOH terminus of SUR1 (ABCC8), we show that this KATP subunit is also expressed in mouse myocardium and is the dominant SUR isoform in the atrium. This suggests differential sarcolemmal KATP composition in atria and ventricles, and, to test this, KATP currents were measured in isolated atrial and ventricular myocytes from wild-type and SUR1−/− animals. KATP conductance is essentially abolished in SUR1−/− atrial myocytes but is normal in SUR1−/− ventricular myocytes. Furthermore, pharmacological properties of wild-type atrial KATP match closely the properties of heterologously expressed SUR1/Kir6.2 channels, whereas ventricular KATP properties match those of heterologously expressed SUR2A/Kir6.2 channels. Collectively, the data demonstrate a previously unappreciated KATP channel heterogeneity: SUR1 is an essential component of atrial, but not ventricular, KATP channels. Differential molecular make-up of the 2 channels underlies differential pharmacology, with important implications when considering sulfonylurea therapy or dissecting the role of cardiac KATP pharmacologically, as well as for understanding of the role of diazoxide in preconditioning.

[1]  T. Flagg,et al.  Role of Sulfonylurea Receptor Type 1 Subunits of ATP-Sensitive Potassium Channels in Myocardial Ischemia/Reperfusion Injury , 2008, Circulation.

[2]  E. Marbán,et al.  Is Kir6.1 a subunit of mitoK(ATP)? , 2008, Biochemical and biophysical research communications.

[3]  N. I. Tavares,et al.  Forkhead Transcription Factors Coordinate Expression of Myocardial KATP Channel Subunits and Energy Metabolism , 2008, Circulation research.

[4]  T. Flagg,et al.  Arrhythmia susceptibility and premature death in transgenic mice overexpressing both SUR1 and Kir6.2[DeltaN30,K185Q] in the heart. , 2007, American journal of physiology. Heart and circulatory physiology.

[5]  J. Zavadil,et al.  Large-scale analysis of ion channel gene expression in the mouse heart during perinatal development. , 2007, Physiological genomics.

[6]  A. Terzic,et al.  KATP channel mutation confers risk for vein of Marshall adrenergic atrial fibrillation , 2007, Nature Clinical Practice Cardiovascular Medicine.

[7]  Colin G. Nichols,et al.  KATP channels as molecular sensors of cellular metabolism , 2006, Nature.

[8]  E. Marbán,et al.  Cardioprotective Role of the Mitochondrial ATP-Binding Cassette Protein 1 , 2005, Circulation research.

[9]  T. Flagg,et al.  Transgenic overexpression of SUR1 in the heart suppresses sarcolemmal K(ATP). , 2005, Journal of molecular and cellular cardiology.

[10]  C. Nichols,et al.  Differential nucleotide regulation of KATP channels by SUR1 and SUR2A. , 2005, Journal of molecular and cellular cardiology.

[11]  M. Artman,et al.  Expression of ATP-Sensitive K+ Channel Subunits during Perinatal Maturation in the Mouse Heart , 2005, Pediatric Research.

[12]  B. O’Rourke,et al.  Mitochondrial K(ATP) channels in cell survival and death. , 2005, Journal of molecular and cellular cardiology.

[13]  Ming Lei,et al.  Specific pattern of ionic channel gene expression associated with pacemaker activity in the mouse heart , 2005, The Journal of physiology.

[14]  E. Marbán,et al.  Multiprotein complex containing succinate dehydrogenase confers mitochondrial ATP-sensitive K+ channel activity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  F. Charpentier,et al.  Remodeling of excitation-contraction coupling in transgenic mice expressing ATP-insensitive sarcolemmal KATP channels. , 2004, American journal of physiology. Heart and circulatory physiology.

[16]  D. Duncker,et al.  Cardioprotective effect of diazoxide is mediated by activation of sarcolemmal but not mitochondrial ATP-sensitive potassium channels in mice. , 2003, Circulation.

[17]  P. Rorsman,et al.  Impaired insulin secretion and glucose tolerance in β cell‐selective CaV1.2 Ca2+ channel null mice , 2003, The EMBO journal.

[18]  R. Hajjar,et al.  Chronic treatment with Carvedilol improves ventricular function and reduces myocyte apoptosis in an animal model of heart failure , 2003, BMC Physiology.

[19]  A. Roatti,et al.  Differential sensitivity of atrial and ventricular K(ATP) channels to metabolic inhibition. , 2003, Cardiovascular research.

[20]  J. Gromada,et al.  Sulfonylurea Receptor Type 1 Knock-out Mice Have Intact Feeding-stimulated Insulin Secretion despite Marked Impairment in Their Response to Glucose* , 2002, The Journal of Biological Chemistry.

[21]  M. Wheeler,et al.  Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels. , 2002, The Journal of clinical investigation.

[22]  S. Seino,et al.  Role of sarcolemmal KATP channels in cardioprotection against ischemia/reperfusion injury in mice , 2002 .

[23]  C. Valdivia,et al.  Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Seino,et al.  Functional Roles of Cardiac and Vascular ATP-Sensitive Potassium Channels Clarified by Kir6.2-Knockout Mice , 2001, Circulation research.

[25]  Yongge Liu,et al.  Pharmacological comparison of native mitochondrial K(ATP) channels with molecularly defined surface K(ATP) channels. , 2001, Molecular pharmacology.

[26]  S. Seino,et al.  Molecular Basis of Electrocardiographic ST-Segment Elevation , 2000, Circulation research.

[27]  E. Marbán,et al.  Selective pharmacological agents implicate mitochondrial but not sarcolemmal K(ATP) channels in ischemic cardioprotection. , 2000, Circulation.

[28]  A. Babenko,et al.  Pharmaco-topology of Sulfonylurea Receptors , 2000, The Journal of Biological Chemistry.

[29]  A. Roatti,et al.  A novel K(ATP) current in cultured neonatal rat atrial appendage cardiomyocytes. , 1999, Circulation research.

[30]  A. Terzic,et al.  Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Yongge Liu,et al.  Pharmacological and histochemical distinctions between molecularly defined sarcolemmal KATP channels and native cardiac mitochondrial KATP channels. , 1999, Molecular pharmacology.

[32]  A. Szewczyk,et al.  Mitochondrial ATP‐Dependent Potassium Channels: Viable Candidate Effectors of Ischemic Preconditioning a , 1999, Annals of the New York Academy of Sciences.

[33]  A. Terzic,et al.  Physical association between recombinant cardiac ATP-sensitive K+ channel subunits Kir6.2 and SUR2A. , 1999, Journal of molecular and cellular cardiology.

[34]  M. Sunagawa,et al.  Antisense oligodeoxynucleotides of sulfonylurea receptors inhibit ATP-sensitive K+ channels in cultured neonatal rat ventricular cells , 1999, Pflügers Archiv.

[35]  A. Babenko,et al.  Reconstituted human cardiac KATP channels: functional identity with the native channels from the sarcolemma of human ventricular cells. , 1998, Circulation research.

[36]  Yongge Liu,et al.  Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection? , 1998, Circulation.

[37]  M. Smith,et al.  Cardioprotective effect of diazoxide and its interaction with mitochondrial ATP-sensitive K+ channels. Possible mechanism of cardioprotection. , 1997, Circulation research.

[38]  C. Nichols,et al.  Regulation of KATP Channel Activity by Diazoxide and MgADP , 1997, The Journal of general physiology.

[39]  L. Cathala,et al.  Neurotensin Inhibition of the Hyperpolarization‐Activated Cation Current (Ih) in the Rat Substantia Nigra Pars Compacta Implicates the Protein Kinase C Pathway , 1997, The Journal of physiology.

[40]  F. Ashcroft,et al.  Truncation of Kir6.2 produces ATP-sensitive K+ channels in the absence of the sulphonylurea receptor , 1997, Nature.

[41]  K. Kunjilwar,et al.  Association and Stoichiometry of KATP Channel Subunits , 1997, Neuron.

[42]  F. Ashcroft,et al.  The essential role of the Walker A motifs of SUR1 in K‐ATP channel activation by Mg‐ADP and diazoxide , 1997, The EMBO journal.

[43]  J. Bryan,et al.  The high-affinity sulfonylurea receptor: distribution, glycosylation, purification, and immunoprecipitation of two forms from endocrine and neuroendocrine cell lines. , 1996, Biochemistry.

[44]  M. Permutt,et al.  Adenosine Diphosphate as an Intracellular Regulator of Insulin Secretion , 1996, Science.

[45]  J. Bryan,et al.  A Family of Sulfonylurea Receptors Determines the Pharmacological Properties of ATP-Sensitive K+ Channels , 1996, Neuron.

[46]  J. Inazawa,et al.  Reconstitution of IKATP: An Inward Rectifier Subunit Plus the Sulfonylurea Receptor , 1995, Science.

[47]  G. Mironova,et al.  Reconstitution and partial purification of the glibenclamide-sensitive, ATP-dependent K+ channel from rat liver and beef heart mitochondria. , 1992, The Journal of biological chemistry.

[48]  T. Higuti,et al.  ATP-sensitive K+ channel in the mitochondrial inner membrane , 1991, Nature.

[49]  S. Seino,et al.  Role of sarcolemmal K(ATP) channels in cardioprotection against ischemia/reperfusion injury in mice. , 2002, The Journal of clinical investigation.

[50]  S Nattel,et al.  Basic mechanisms of atrial fibrillation--very new insights into very old ideas. , 2000, Annual review of physiology.

[51]  L. Aguilar-Bryan,et al.  Sur1 Knockout Mice A MODEL FOR K ATP CHANNEL-INDEPENDENT REGULATION OF INSULIN SECRETION* , 2000 .

[52]  S. Seino.  ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. , 1999, Annual review of physiology.

[53]  F. Ashcroft,et al.  Properties of cloned ATP‐sensitive K+ currents expressed in Xenopus oocytes. , 1997, The Journal of physiology.