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 (Zn2+) but also copper (Cu2+) and protons (H+) are agonists of ZAC, displaying potencies and efficacies in the rank orders of H+ > Cu2+ > Zn2+ and H+ > Zn2+ > Cu2+, respectively. The responses elicited by Zn2+, Cu2+ 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 Ca2+ or Mg2+ results in complete elimination of Zn2+-activated currents at both negative and positive holding potentials. This indicates that ZAC is non-selectively permeable to monovalent cations, whereas Ca2+ and Mg2+ inhibit the channel. In conclusion, this is the first report of a Cys-loop receptor being gated by Zn2+, Cu2+ and H+. ZAC could be an important mediator of some of the wide range of physiological functions regulated by or involving Zn2+, Cu2+ and H+.

Fluorescence-detection size-exclusion chromatography utilizing nanobody technology for expression screening of membrane proteins

“…4 and 5). ZACs belong to the Cys-loop ligand-gated ion channel (LGIC) superfamily, which also includes nicotinic acetylcholine (nACh), 5-HT 3 , GABA A and glycine receptors 47, 48 .…”

“…In addition to Zn 2+ , the gating of ZACs, nonselective cation channels that are widely expressed in the human body, is activated by Cu 2+ and protons 48 . Since ZACs were the last members of the Cys-loop LGIC superfamily to be discovered 47–49 , their function and structure are poorly characterized.…”

ZAC (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

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The zinc-activated channel (ZAC, nomenclature as agreed by the NC-IUPHAR Subcommittee for the Zinc Activated Channel) is a member of the Cys-loop family that includes the nicotinic ACh, 5-HT 3 , GABA A and strychnine-sensitive glycine receptors [1,2,3]. The channel is likely to exist as a homopentamer of 4TM subunits that form an intrinsic cation selective channel equipermeable to Na + , K + and Cs + , but impermeable to Ca 2+ and Mg 2+ [3]. ZAC displays constitutive activity that can be blocked by tubocurarine and high concentrations of Ca 2+ [3].

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“…The channel is likely to exist as a homopentamer of 4TM subunits that form an intrinsic cation selective channel equipermeable to Na + , K + and Cs + , but impermeable to Ca 2+ and Mg 2+ [3]. ZAC displays constitutive activity that can be blocked by tubocurarine and high concentrations of Ca 2+ [3]. Although denoted ZAC, the channel is more potently activated by protons and copper, with greater and lesser efficacy than zinc, respectively [3].…”

“…ZAC displays constitutive activity that can be blocked by tubocurarine and high concentrations of Ca 2+ [3]. Although denoted ZAC, the channel is more potently activated by protons and copper, with greater and lesser efficacy than zinc, respectively [3]. ZAC is present in the human, chimpanzee, dog, cow and opossum genomes, but is functionally absent from mouse, or rat, genomes [1,2].…”