Role of homologous ASP334 and GLU319 in human non-gastric H,K- and Na,K-ATPases in cardiac glycoside binding

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Serveur académique Lausannois

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info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bbrc.2007.02.119

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info:eu-repo/semantics/altIdentifier/pmid/17349614

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info:eu-repo/semantics/altIdentifier/pissn/0006-291X

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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_C653864473A88

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Serveur Académique Lausannois

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Université de Lausanne et CHUV

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Amino Acid Sequence *Amino Acid Substitution Animals Aspartic Acid/genetics Binding, Competitive/drug effects Biological Transport/drug effects Cardiac Glycosides/*metabolism Dose-Response Relationship, Drug Enzyme Inhibitors/pharmacology Female Glutamic Acid/genetics H(+)-K(+)-Exchanging ATPase/antagonists & inhibitors/genetics/*metabolism Humans Membrane Potentials/drug effects Mutation Na(+)-K(+)-Exchanging ATPase/antagonists & inhibitors/genetics/*metabolism Oocytes/drug effects/metabolism/physiology Ouabain/analogs & derivatives/pharmacology Protein Subunits/antagonists & inhibitors/genetics/metabolism Rabbits Rats Rubidium Radioisotopes/pharmacokinetics Sequence Homology, Amino Acid Xenopus laevis

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R. Radkov et al., « Role of homologous ASP334 and GLU319 in human non-gastric H,K- and Na,K-ATPases in cardiac glycoside binding », Serveur académique Lausannois, ID : 10.1016/j.bbrc.2007.02.119

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Cardiac steroids inhibit Na,K-ATPase and the related non-gastric H,K-ATPase, while they do not interact with gastric H,K-ATPase. Introducing an arginine, the residue present in the gastric H,K-ATPase, in the second extracellular loop at the corresponding position 334 in the human non-gastric H,K-ATPase (D334R mutation) rendered it completely resistant to 2mM ouabain. The corresponding mutation (E319R) in alpha1 Na,K-ATPase produced a approximately 2-fold increase of the ouabain IC(50) in the ouabain-resistant rat alpha1 Na,K-ATPase and a large decrease of the ouabain affinity of human alpha1 Na,K-ATPase, on the other hand this mutation had no effect on the affinity for the aglycone ouabagenin. These results provide a strong support for the orientation of ouabain in its biding site with its sugar moiety interacting directly with the second extracellular loop.

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