![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Institut de Pharmacologie et de Toxicologie, Université de Lausanne, Lausanne, Switzerland
The epithelial Na+ channel ENaC mediates transepithelial Na+ transport in the distal kidney, the colon, and the lung and is a key element for the maintenance of Na+ balance and the regulation of blood pressure. Mutagenesis studies have identified residues 
S583 and the homologous 
G525 and 
G537 in the outer pore entrance that are critical for ENaC block by the K+-sparing diuretic amiloride. The aim of the present study was to determine first, whether these residues are part of the amiloride binding site, and second, whether they are general determinants of ENaC block by amiloride and its derivatives. Kinetic analysis of the association and dissociation rates of amiloride and benzamil to ENaC showed that mutation of residue S583C and the homologous G525C increased the dissociation rate of the drugs from the binding site, with little changes in their association rate. Thus, these mutations destabilize the binding interaction between the blockers and the receptor on the channel, favoring the unbinding of the ligand. This strongly suggests that they are part of the binding site. Because mutations of S583, G525, and G537 have similar effects on amiloride, benzamil, and triamterene block, we conclude that these three ENaC blockers share a common receptor within the ion channel pore.
Received April 30, 2003; accepted June 24, 2003.
Address correspondence to: Dr. Stephan Kellenberger, Institut de Pharmacologie et de Toxicologie, Bugnon 27, Université de Lausanne CH-1005, Lausanne Suisse, Switzerland. E-mail: stephan.kellenberger{at}ipharm.unil.ch
This article has been cited by other articles:
|
|
 |
|
  H.-G. Nie, T. Tucker, X.-F. Su, T. Na, J.-B. Peng, P. R. Smith, S. Idell, and H.-L. Ji Expression and Regulation of Epithelial Na+ Channels by Nucleotides in Pleural Mesothelial Cells Am. J. Respir. Cell Mol. Biol., May 1, 2009; 40(5): 543 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Hirsh, J. Zhang, A. Zamurs, J. Fleegle, W. R. Thelin, R. A. Caldwell, J. R. Sabater, W. M. Abraham, M. Donowitz, B. Cha, et al. Pharmacological Properties of N-(3,5-Diamino-6-chloropyrazine-2-carbonyl)-N'-4-[4-(2,3-dihydroxypropoxy)phenyl]butyl-guanidine Methanesulfonate (552-02), a Novel Epithelial Sodium Channel Blocker with Potential Clinical Efficacy for Cystic Fibrosis Lung Disease J. Pharmacol. Exp. Ther., April 1, 2008; 325(1): 77 - 88. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. O'Brodovich, P. Yang, S. Gandhi, and G. Otulakowski Amiloride-insensitive Na+ and fluid absorption in the mammalian distal lung Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L401 - L408. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Shigemura, T. Ohkuri, C. Sadamitsu, K. Yasumatsu, R. Yoshida, G. K. Beauchamp, A. A. Bachmanov, and Y. Ninomiya Amiloride-sensitive NaCl taste responses are associated with genetic variation of ENaC {alpha}-subunit in mice Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2008; 294(1): R66 - R75. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A.-N. Takeda, I. Gautschi, M. X. van Bemmelen, and L. Schild Cadmium Trapping in an Epithelial Sodium Channel Pore Mutant J. Biol. Chem., November 2, 2007; 282(44): 31928 - 31936. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Anantharam and L. G. Palmer Determination of Epithelial Na+ Channel Subunit Stoichiometry from Single-Channel Conductances J. Gen. Physiol., July 1, 2007; 130(1): 55 - 70. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Brown, S. M. Fernandez-Illescas, Z. Liao, and M. B. Goodman Gain-of-Function Mutations in the MEC-4 DEG/ENaC Sensory Mechanotransduction Channel Alter Gating and Drug Blockade J. Gen. Physiol., January 29, 2007; 129(2): 161 - 173. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Ohkuri, K. Yasumatsu, N. Shigemura, R. Yoshida, and Y. Ninomiya Amiloride Inhibition on NaCl Responses of the Chorda Tympani Nerve in Two 129 Substrains of Mice, 129P3/J and 129X1/SvJ Chem Senses, July 1, 2006; 31(6): 565 - 572. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Pfister, I. Gautschi, A.-N. Takeda, M. van Bemmelen, S. Kellenberger, and L. Schild A Gating Mutation in the Internal Pore of ASIC1a J. Biol. Chem., April 28, 2006; 281(17): 11787 - 11791. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Royal, L. Bianchi, M. A. Royal, M. Lizzio Jr., G. Mukherjee, Y. O. Nunez, and M. Driscoll Temperature-sensitive Mutant of the Caenorhabditis elegans Neurotoxic MEC-4(d) DEG/ENaC Channel Identifies a Site Required for Trafficking or Surface Maintenance J. Biol. Chem., December 23, 2005; 280(51): 41976 - 41986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Loffing and L. Schild Functional Domains of the Epithelial Sodium Channel J. Am. Soc. Nephrol., November 1, 2005; 16(11): 3175 - 3181. [Full Text] [PDF]
|
|
|
|
 |
|
 D. Cucu, J. Simaels, J. Eggermont, W. Van Driessche, and W. Zeiske Opposite effects of Ni2+ on Xenopus and rat ENaCs expressed in Xenopus oocytes Am J Physiol Cell Physiol, October 1, 2005; 289(4): C946 - C958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. B. Kashlan, S. Sheng, and T. R. Kleyman On the Interaction between Amiloride and Its Putative {alpha}-Subunit Epithelial Na+ Channel Binding Site J. Biol. Chem., July 15, 2005; 280(28): 26206 - 26215. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kellenberger, I. Gautschi, Y. Pfister, and L. Schild Intracellular Thiol-mediated Modulation of Epithelial Sodium Channel Activity J. Biol. Chem., March 4, 2005; 280(9): 7739 - 7747. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Butterworth, R. S. Edinger, J. P. Johnson, and R. A. Frizzell Acute ENaC Stimulation by cAMP in a Kidney Cell Line is Mediated by Exocytic Insertion from a Recycling Channel Pool J. Gen. Physiol., December 28, 2004; 125(1): 81 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-L. Ji and D. J. Benos Degenerin Sites Mediate Proton Activation of {delta}{beta}{gamma}-Epithelial Sodium Channel J. Biol. Chem., June 25, 2004; 279(26): 26939 - 26947. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
