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-HT₃, GABA_A and strychnine-sensitive glycine receptors [1-2,4]. 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 Ca²⁺ and Mg²⁺ [4]. ZAC displays constitutive activity that can be blocked by tubocurarine, TTFB and high concentrations of Ca²⁺ [4]. Although denoted ZAC, the channel is more potently activated by H⁺ and Cu²⁺, with greater and lesser efficacy than Zn²⁺, respectively [4]. Orthologs of the human ZACN gene are present in a wide range of mammalian genomes, but notably not in the mouse or rat genomes. [1-2].

A ZACN gene does not appear to exist in the mouse or rat genomes [1]. Although tabulated as an antagonist, it is possible that tubocurarine acts as a channel blocker. Antagonism by Ca²⁺ is voltage-independent. ZAC is not activated (at 1 mM) by transition metals including Fe²⁺, Co²⁺, Ni²⁺, Cd²⁺, or Al³⁺ [4]. The concentration response relationship to Cu²⁺ is biphasic, with concentrations exceeding 30 μM being associated with reduced activation [4]. The N-(thiazol-2-yl)-benzamide analog TTFB has been identified as a moderately potent negative allosteric modulator of ZAC. TTFB displays negligible activity at representatives of the GABA_A, glycine, 5-HT₃ and nicotinic ACh receptors, and thus it constitutes a potential pharmacological tool for ZAC.

* Key recommended reading is highlighted with an asterisk

* Collingridge GL, Olsen RW, Peters J, Spedding M. (2009) A nomenclature for ligand-gated ion channels. Neuropharmacology, 56 (1): 2-5. [PMID:18655795]

* Madjroh N, Davies PA, Smalley JL, Kristiansen U, Söderhielm PC, Jensen AA. (2021) Delineation of the functional properties exhibited by the Zinc-Activated Channel (ZAC) and its high-frequency Thr¹²⁸Ala variant (rs2257020) in Xenopus oocytes. Pharmacol Res, 169: 105653. [PMID:33962015]

* Madjroh N, Mellou E, Davies PA, Söderhielm PC, Jensen AA. (2021) Discovery and functional characterization of N-(thiazol-2-yl)-benzamide analogs as the first class of selective antagonists of the Zinc-Activated Channel (ZAC). Biochem Pharmacol, 193: 114782. [PMID:34560054]

* Madjroh N, Mellou E, Æbelø L, Davies PA, Söderhielm PC, Jensen AA. (2021) Probing the molecular basis for signal transduction through the Zinc-Activated Channel (ZAC). Biochem Pharmacol,: 114781 [Epub ahead of print]. [PMID:34560053]

* Peralta FA, Huidobro-Toro JP. (2016) Zinc as Allosteric Ion Channel Modulator: Ionotropic Receptors as Metalloproteins. Int J Mol Sci, 17 (7). [PMID:27384555]

* Trattnig SM, Gasiorek A, Deeb TZ, Ortiz EJ, Moss SJ, Jensen AA, Davies PA. (2016) Copper and protons directly activate the zinc-activated channel. Biochem Pharmacol, 103: 109-17. [PMID:26872532]

1. Davies PA, Wang W, Hales TG, Kirkness EF. (2003) A novel class of ligand-gated ion channel is activated by Zn2+. J Biol Chem, 278 (2): 712-7. [PMID:12381728]

2. Houtani T, Munemoto Y, Kase M, Sakuma S, Tsutsumi T, Sugimoto T. (2005) Cloning and expression of ligand-gated ion-channel receptor L2 in central nervous system. Biochem Biophys Res Commun, 335 (2): 277-85. [PMID:16083862]

3. Madjroh N, Mellou E, Davies PA, Söderhielm PC, Jensen AA. (2021) Discovery and functional characterization of N-(thiazol-2-yl)-benzamide analogs as the first class of selective antagonists of the Zinc-Activated Channel (ZAC). Biochem Pharmacol, 193: 114782. [PMID:34560054]

4. Trattnig SM, Gasiorek A, Deeb TZ, Ortiz EJ, Moss SJ, Jensen AA, Davies PA. (2016) Copper and protons directly activate the zinc-activated channel. Biochem Pharmacol, 103: 109-17. [PMID:26872532]