title: Bile acids potentiate proton-activated currents inXenopus laevisoocytes expressing human acid-sensing ion channel (ASIC1a).
abstract: Acid-sensing ion channels (ASICs) are nonvoltage-gated sodium channels transiently activated by extracellular protons and belong to the epithelial sodium channel (ENaC)/Degenerin (DEG) family of ion channels. Bile acids have been shown to activate two members of this family, the bile acid-sensitive ion channel (BASIC) and ENaC. To investigate whether bile acids also modulate ASIC function, human ASIC1a was heterologously expressed inXenopus laevisoocytes. Exposing oocytes to tauro-conjugated cholic (t-CA), deoxycholic (t-DCA), and chenodeoxycholic (t-CDCA) acid at pH 7.4 did not activate ASIC1a-mediated whole-cell currents. However, in ASIC1a expressing oocytes the whole-cell currents elicited by pH 5.5 were significantly increased in the presence of these bile acids. Single-channel recordings in outside-out patches confirmed that t-DCA enhanced the stimulatory effect of pH 5.5 on ASIC1a channel activity. Interestingly, t-DCA reduced single-channel current amplitude by ~15% which suggests an interaction of t-DCA with a region close to the channel pore. Molecular docking predicted binding of bile acids to the pore region near the degenerin site (G433) in the open conformation of the channel. Site-directed mutagenesis demonstrated that the amino acid residue G433 is critically involved in the potentiating effect of bile acids on ASIC1a activation by protons.
authors.affiliation: Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Alexandr V
authors.initials: AV
authors.lastname: Ilyaskin
authors.affiliation: Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Alexei
authors.initials: A
authors.lastname: Diakov
authors.affiliation: Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany christoph.korbmacher@fau.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Korbmacher
authors.affiliation: Institut für Zelluläre und Molekulare Physiologie, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Haerteis
mesh_terms: D062565:Acid Sensing Ion Channels / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D001665:Binding Sites; D006801:Humans; D006863:Hydrogen-Ion Concentration; D062105:Molecular Docking Simulation; D009865:Oocytes; D011522:Protons; D014982:Xenopus laevis
chemical_list: C568266:ASIC1 protein, human; D062565:Acid Sensing Ion Channels; D001647:Bile Acids and Salts; D011522:Protons
keywords: Acid‐sensing ion channel 1a (ASIC1a); bile acids; degenerin site; patch clamp