Original Article

Trapping of a Methanesulfonanilide by Closure of the HERG Potassium Channel Activation Gate

Correspondence to: John S. Mitcheson, Eccles Institute of Human Genetics, University of Utah, 15 North 2030 East, Rm. 4220, Salt Lake City, UT 84112. Fax:801-585-3501 E-mail:john.mitcheson{at}hci.utah.edu.

Released online: 14 February 2000

Deactivation of voltage-gated potassium (K⁺) channels can slow or prevent the recovery from block by charged organic compounds, a phenomenon attributed to trapping of the compound within the inner vestibule by closure of the activation gate. Unbinding and exit from the channel vestibule of a positively charged organic compound should be favored by membrane hyperpolarization if not impeded by the closed gate. MK-499, a methanesulfonanilide compound, is a potent blocker (IC₅₀ = 32 nM) of HERG K⁺ channels. This bulky compound (7 x 20 Å) is positively charged at physiological pH. Recovery from block of HERG channels by MK-499 and other methanesulfonanilides is extremely slow (Carmeliet 1992 ; Ficker et al. 1998 ), suggesting a trapping mechanism. We used a mutant HERG (D540K) channel expressed in Xenopus oocytes to test the trapping hypothesis. D540K HERG has the unusual property of opening in response to hyperpolarization, in addition to relatively normal gating and channel opening in response to depolarization (Sanguinetti and Xu 1999 ). The hyperpolarization-activated state of HERG was characterized by long bursts of single channel reopening. Channel reopening allowed recovery from block by 2 µM MK-499 to occur with time constants of 10.5 and 52.7 s at -160 mV. In contrast, wild-type HERG channels opened only briefly after membrane hyperpolarization, and thus did not permit recovery from block by MK-499. These findings provide direct evidence that the mechanism of slow recovery from HERG channel block by methanesulfonanilides is due to trapping of the compound in the inner vestibule by closure of the activation gate. The ability of HERG channels to trap MK-499, despite its large size, suggests that the vestibule of this channel is larger than the well studied Shaker K⁺ channel.

Key Words: MK-499, voltage clamp, Xenopus oocyte

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				S. L. Wynia-Smith, A. L. Gillian-Daniel, K. A. Satyshur, and G. A. Robertson hERG Gating Microdomains Defined by S6 Mutagenesis and Molecular Modeling J. Gen. Physiol., October 27, 2008; 132(5): 507 - 520. [Abstract] [Full Text] [PDF]

				H. Sale, J. Wang, T. J. O'Hara, D. J. Tester, P. Phartiyal, J.-Q. He, Y. Rudy, M. J. Ackerman, and G. A. Robertson Physiological Properties of hERG 1a/1b Heteromeric Currents and a hERG 1b-Specific Mutation Associated With Long-QT Syndrome Circ. Res., September 26, 2008; 103(7): e81 - e95. [Abstract] [Full Text] [PDF]

				M. A. Pineros, G. M.A. Cancado, and L. V. Kochian Novel Properties of the Wheat Aluminum Tolerance Organic Acid Transporter (TaALMT1) Revealed by Electrophysiological Characterization in Xenopus Oocytes: Functional and Structural Implications Plant Physiology, August 1, 2008; 147(4): 2131 - 2146. [Abstract] [Full Text] [PDF]

				J. C. Hancox and A. F. James Refining Insights into High-Affinity Drug Binding to the Human Ether-a-go-go-Related Gene Potassium Channel Mol. Pharmacol., June 1, 2008; 73(6): 1592 - 1595. [Abstract] [Full Text] [PDF]

				R. M. Hardman, P. J. Stansfeld, S. Dalibalta, M. J. Sutcliffe, and J. S. Mitcheson Activation Gating of hERG Potassium Channels: S6 GLYCINES ARE NOT REQUIRED AS GATING HINGES J. Biol. Chem., November 2, 2007; 282(44): 31972 - 31981. [Abstract] [Full Text] [PDF]

				T. Nakajima, K. Hayashi, P. C. Viswanathan, M.-Y. Kim, M. Anghelescu, K. A. Barksdale, W. Shuai, J. R. Balser, and S. Kupershmidt HERG Is Protected from Pharmacological Block by {alpha}-1,2-Glucosyltransferase Function J. Biol. Chem., February 23, 2007; 282(8): 5506 - 5513. [Abstract] [Full Text] [PDF]

				O. A. Hoekenga, L. G. Maron, M. A. Pineros, G. M. A. Cancado, J. Shaff, Y. Kobayashi, P. R. Ryan, B. Dong, E. Delhaize, T. Sasaki, et al. From the Cover: AtALMT1, which encodes a malate transporter, is identified as one of several genes critical for aluminum tolerance in Arabidopsis PNAS, June 20, 2006; 103(25): 9738 - 9743. [Abstract] [Full Text] [PDF]

				K. Kamiya, R. Niwa, J. S. Mitcheson, and M. C. Sanguinetti Molecular Determinants of hERG Channel Block Mol. Pharmacol., May 1, 2006; 69(5): 1709 - 1716. [Abstract] [Full Text] [PDF]

				S. L. Cockerill and J. S. Mitcheson Direct Block of Human Ether-a-go-go-Related Gene Potassium Channels by Caffeine J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 860 - 868. [Abstract] [Full Text] [PDF]

				M. Perry, P. J. Stansfeld, J. Leaney, C. Wood, M. J. de Groot, D. Leishman, M. J. Sutcliffe, and J. S. Mitcheson Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs Mol. Pharmacol., February 1, 2006; 69(2): 509 - 519. [Abstract] [Full Text] [PDF]

				J. Lin, J. Guo, H. Gang, P. Wojciechowski, J. T. Wigle, and S. Zhang Intracellular K+ Is Required for the Inactivation-Induced High-Affinity Binding of Cisapride to HERG Channels Mol. Pharmacol., September 1, 2005; 68(3): 855 - 865. [Abstract] [Full Text] [PDF]

				C. E. Clancy and R. S. Kass Inherited and Acquired Vulnerability to Ventricular Arrhythmias: Cardiac Na+ and K+ Channels Physiol Rev, January 1, 2005; 85(1): 33 - 47. [Abstract] [Full Text] [PDF]

				D. Thomas, B. C. Hammerling, A.-B. Wimmer, K. Wu, E. Ficker, Y. A. Kuryshev, D. Scherer, J. Kiehn, H. A. Katus, W. Schoels, et al. Direct block of hERG potassium channels by the protein kinase C inhibitor bisindolylmaleimide I (GF109203X) Cardiovasc Res, December 1, 2004; 64(3): 467 - 476. [Abstract] [Full Text] [PDF]

				H. J. Witchel, C. E. Dempsey, R. B. Sessions, M. Perry, J. T. Milnes, J. C. Hancox, and J. S. Mitcheson The Low-Potency, Voltage-Dependent HERG Blocker Propafenone--Molecular Determinants and Drug Trapping Mol. Pharmacol., November 1, 2004; 66(5): 1201 - 1212. [Abstract] [Full Text] [PDF]

				J.-S. Bian, A. Kagan, and T. V. McDonald Molecular analysis of PIP2 regulation of HERG and IKr Am J Physiol Heart Circ Physiol, November 1, 2004; 287(5): H2154 - H2163. [Abstract] [Full Text] [PDF]

				R. E. Garcia-Ferreiro, D. Kerschensteiner, F. Major, F. Monje, W. Stuhmer, and L. A. Pardo Mechanism of Block of hEag1 K+ Channels by Imipramine and Astemizole J. Gen. Physiol., September 27, 2004; 124(4): 301 - 317. [Abstract] [Full Text] [PDF]

				M. Perry, M. J. de Groot, R. Helliwell, D. Leishman, M. Tristani-Firouzi, M. C. Sanguinetti, and J. Mitcheson Structural Determinants of HERG Channel Block by Clofilium and Ibutilide Mol. Pharmacol., August 1, 2004; 66(2): 240 - 249. [Abstract] [Full Text] [PDF]

				F. M. Mullins, S. Z. Stepanovic, N. B. Gillani, A. L. George Jr, and J. R. Balser Functional interaction between extracellular sodium, potassium and inactivation gating in HERG channels J. Physiol., August 1, 2004; 558(3): 729 - 744. [Abstract] [Full Text] [PDF]

				P. Westenskow, I. Splawski, K. W. Timothy, M. T. Keating, and M. C. Sanguinetti Compound Mutations: A Common Cause of Severe Long-QT Syndrome Circulation, April 20, 2004; 109(15): 1834 - 1841. [Abstract] [Full Text] [PDF]

				J. Tamargo, R. Caballero, R. Gomez, C. Valenzuela, and E. Delpon Pharmacology of cardiac potassium channels Cardiovasc Res, April 1, 2004; 62(1): 9 - 33. [Abstract] [Full Text] [PDF]

				D. Fernandez, A. Ghanta, G. W. Kauffman, and M. C. Sanguinetti Physicochemical Features of the hERG Channel Drug Binding Site J. Biol. Chem., March 12, 2004; 279(11): 10120 - 10127. [Abstract] [Full Text] [PDF]

				R. Brugada, K. Hong, R. Dumaine, J. Cordeiro, F. Gaita, M. Borggrefe, T. M. Menendez, J. Brugada, G. D. Pollevick, C. Wolpert, et al. Sudden Death Associated With Short-QT Syndrome Linked to Mutations in HERG Circulation, January 6, 2004; 109(1): 30 - 35. [Abstract] [Full Text] [PDF]

				G. Seebohm, J. Chen, N. Strutz, C. Culberson, C. Lerche, and M. C. Sanguinetti Molecular Determinants of KCNQ1 Channel Block by a Benzodiazepine Mol. Pharmacol., July 1, 2003; 64(1): 70 - 77. [Abstract] [Full Text] [PDF]

				M. Zhang, Y. V. Korolkova, J. Liu, M. Jiang, E. V. Grishin, and G.-N. Tseng BeKm-1 Is a HERG-Specific Toxin that Shares the Structure with ChTx but the Mechanism of Action with ErgTx1 Biophys. J., May 1, 2003; 84(5): 3022 - 3036. [Abstract] [Full Text] [PDF]

				K. Ishii, M. Nagai, M. Takahashi, and M. Endoh Dissociation of E-4031 from the HERG channel caused by mutations of an amino acid results in greater block at high stimulation frequency Cardiovasc Res, March 1, 2003; 57(3): 651 - 659. [Abstract] [Full Text] [PDF]

				J. Wang, K. Della Penna, H. Wang, J. Karczewski, T. M. Connolly, K. S. Koblan, P. B. Bennett, and J. J. Salata Functional and pharmacological properties of canine ERG potassium channels Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H256 - H267. [Abstract] [Full Text] [PDF]

				J. Liu, M. Zhang, M. Jiang, and G.-N. Tseng Structural and Functional Role of the Extracellular S5-P Linker in the HERG Potassium Channel J. Gen. Physiol., October 29, 2002; 120(5): 723 - 737. [Abstract] [Full Text] [PDF]

				H. P. Larsson The Search Is on for the Voltage Sensor-to-gate Coupling J. Gen. Physiol., September 30, 2002; 120(4): 475 - 481. [Full Text] [PDF]

				J. Chen, G. Seebohm, and M. C. Sanguinetti Position of aromatic residues in the S6 domain, not inactivation, dictates cisapride sensitivity of HERG and eag potassium channels PNAS, September 17, 2002; 99(19): 12461 - 12466. [Abstract] [Full Text] [PDF]

				M. Mbai, S. Rajamani, and C. T January The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels Cardiovasc Res, September 1, 2002; 55(4): 799 - 805. [Abstract] [Full Text] [PDF]

				W. A. Volberg, B. J. Koci, W. Su, J. Lin, and J. Zhou Blockade of Human Cardiac Potassium Channel Human Ether-a-go-go-Related Gene (HERG) by Macrolide Antibiotics J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 320 - 327. [Abstract] [Full Text] [PDF]

				M. Tristani-Firouzi, J. Chen, and M. C. Sanguinetti Interactions between S4-S5 Linker and S6 Transmembrane Domain Modulate Gating of HERG K+ Channels J. Biol. Chem., May 17, 2002; 277(21): 18994 - 19000. [Abstract] [Full Text] [PDF]

				D. Thomas, B. Gut, G. Wendt-Nordahl, and J. Kiehn The Antidepressant Drug Fluoxetine Is an Inhibitor of Human Ether-A-Go-Go-Related Gene (HERG) Potassium Channels J. Pharmacol. Exp. Ther., February 1, 2002; 300(2): 543 - 548. [Abstract] [Full Text] [PDF]

				E. Ficker, W. Jarolimek, and A. M. Brown Molecular Determinants of Inactivation and Dofetilide Block in ether a-go-go (EAG) Channels and EAG-Related K+ Channels Mol. Pharmacol., December 1, 2001; 60(6): 1343 - 1348. [Abstract] [Full Text] [PDF]

				K. Kamiya, J. S. Mitcheson, K. Yasui, I. Kodama, and M. C. Sanguinetti Open Channel Block of HERG K+ Channels by Vesnarinone Mol. Pharmacol., August 1, 2001; 60(2): 244 - 253. [Abstract] [Full Text] [PDF]

				S. Zhang, S. Rajamani, Y. Chen, Q. Gong, Y. Rong, Z. Zhou, A. Ruoho, and C. T. January Cocaine Blocks HERG, but Not KvLQT1+minK, Potassium Channels Mol. Pharmacol., April 16, 2001; 59(5): 1069 - 1076. [Abstract] [Full Text]

				D. Thomas, G. Wendt-Nordahl, K. Röckl, E. Ficker, A. M. Brown, and J. Kiehn High-Affinity Blockade of Human Ether-A-Go-Go-Related Gene Human Cardiac Potassium Channels by the Novel Antiarrhythmic Drug BRL-32872 J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 753 - 761. [Abstract] [Full Text]

				M. E. O'Leary Inhibition of Human Ether-A-Go-Go Potassium Channels by Cocaine Mol. Pharmacol., February 1, 2001; 59(2): 269 - 277. [Abstract] [Full Text]

				H. Numaguchi, F. M. Mullins, J. P. Johnson Jr., D. C. Johns, S. S. Po, I. C.-H. Yang, G. F. Tomaselli, and J. R. Balser Probing the Interaction Between Inactivation Gating and Dd-Sotalol Block of HERG Circ. Res., November 24, 2000; 87(11): 1012 - 1018. [Abstract] [Full Text] [PDF]

				R. S. Kass and C. Cabo Channel structure and drug-induced cardiac arrhythmias PNAS, October 24, 2000; 97(22): 11683 - 11684. [Full Text] [PDF]

				J. S. Mitcheson, J. Chen, M. Lin, C. Culberson, and M. C. Sanguinetti A structural basis for drug-induced long QT syndrome PNAS, September 22, 2000; (2000) 210244497. [Abstract] [Full Text]

				J. Chen, J. S. Mitcheson, M. Lin, and M. C. Sanguinetti Functional Roles of Charged Residues in the Putative Voltage Sensor of the HCN2 Pacemaker Channel J. Biol. Chem., November 10, 2000; 275(46): 36465 - 36471. [Abstract] [Full Text] [PDF]

				J. S. Mitcheson, J. Chen, M. Lin, C. Culberson, and M. C. Sanguinetti A structural basis for drug-induced long QT syndrome PNAS, October 24, 2000; 97(22): 12329 - 12333. [Abstract] [Full Text] [PDF]

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents