title: Copper and protons directly activate the zinc-activated channel.
abstract: The zinc-activated channel (ZAC) is a cationic ion channel belonging to the superfamily of Cys-loop receptors, which consists of pentameric ligand-gated ion channels. ZAC is the least understood member of this family so in the present study we sought to characterize the properties of this channel further. We demonstrate that not only zinc (Zn(2+)) but also copper (Cu(2+)) and protons (H(+)) are agonists of ZAC, displaying potencies and efficacies in the rank orders of H(+)>Cu(2+)>Zn(2+) and H(+)>Zn(2+)>Cu(2+), respectively. The responses elicited by Zn(2+), Cu(2+) and H(+) through ZAC are all characterized by low degrees of desensitization. In contrast, currents evoked by high concentrations of the three agonists comprise distinctly different activation and decay components, with transitions to and from an open state being significantly faster for H(+) than for the two metal ions. The permeabilities of ZAC for Na(+) and K(+) relative to Cs(+) are indistinguishable, whereas replacing all of extracellular Na(+) and K(+) with the divalent cations Ca(2+) or Mg(2+) results in complete elimination of Zn(2+)-activated currents at both negative and positive holding potentials. This indicates that ZAC is non-selectively permeable to monovalent cations, whereas Ca(2+) and Mg(2+) inhibit the channel. In conclusion, this is the first report of a Cys-loop receptor being gated by Zn(2+), Cu(2+) and H(+). ZAC could be an important mediator of some of the wide range of physiological functions regulated by or involving Zn(2+), Cu(2+) and H(+).
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: sarahmaria.trattnig@gmail.com.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Trattnig
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: agnes.gasiorek@sund.ku.dk.
authors.forename: Agnes
authors.initials: A
authors.lastname: Gasiorek
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: Tarek.Deeb@tufts.edu.
authors.forename: Tarek Z
authors.initials: TZ
authors.lastname: Deeb
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: eydith@gmail.com.
authors.forename: Eydith J Comenencia
authors.initials: EJ
authors.lastname: Ortiz
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: Stephen.Moss@tufts.edu.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: aaj@sund.ku.dk.
authors.forename: Anders A
authors.initials: AA
authors.lastname: Jensen
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02111, USA. Electronic address: paul.davies@tufts.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davies
mesh_terms: D000818:Animals; D019556:COS Cells; D002413:Cations, Divalent; D002414:Cations, Monovalent; D002522:Chlorocebus aethiops; D003300:Copper / Q000494:pharmacology*; D005998:Glycine / Q000494:pharmacology; D057809:HEK293 Cells; D006639:Histidine / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D011522:Protons; D015032:Zinc / Q000494:pharmacology*
chemical_list: D002413:Cations, Divalent; D002414:Cations, Monovalent; D007473:Ion Channels; D009942:Organometallic Compounds; D011522:Protons; C052388:zinc-histidine complex; D006639:Histidine; C018493:cupric glycinate; D003300:Copper; D015032:Zinc; D005998:Glycine
keywords: Calcium block; Copper; Cys-loop ligand-gated ion channels; Protons; Zinc