Discovery and functional characterization of N-(thiazol-2-yl)-benzamide analogs as the first class of selective antagonists of the Zinc-Activated Channel (ZAC)

Madjroh, Nawid; Mellou, Eleni; Davies, Paul; Söderhielm, Pella Cecilia; Jensen, Anders A.

doi:10.1016/j.bcp.2021.114782

Cited by 2 publications

(1 citation statement)

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“…Representative examples of current traces evoked by different Zn 2+ concentrations are given in Figures 3, 4, the mean concentrationresponse relationships determined for the metal ion at the seven receptors are given in Figure 5, and the mean pharmacological properties extracted from the experiments are presented in Table 2. In agreement with previous studies of wild-type (untagged) human ZAC in oocytes (Madjroh et al, 2021a;Madjroh et al, 2021b;Madjroh et al, 2021c), Zn 2+ displayed an EC 50 value of 0.71 mM and a Hill slope of 2.6 ± 0.2 at hsZAC (Table 2). Analogously, Zn 2+ induced robust current responses in a concentration-dependent manner in oocytes expressing the six other mammalian ZACs and displayed comparable concentration-response relationships at these receptors (Figures 3-5).…”

Section: Functional Properties Displayed By 7 Mammalian Zacs In Xenop...supporting

confidence: 92%

Evolutionary conservation of Zinc-Activated Channel (ZAC) functionality in mammals: a range of mammalian ZACs assemble into cell surface-expressed functional receptors

Jensen

2023

Front. Mol. Biosci.

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In contrast to the other pentameric ligand-gated ion channels in the Cys-loop receptor superfamily, the ZACN gene encoding for the Zinc-Activated Channel (ZAC) is exclusively found in the mammalian genome. Human ZAC assembles into homomeric cation-selective channels gated by Zn2+, Cu2+ and H+, but the function of the receptor in human physiology is presently poorly understood. In this study, the degree of evolutionary conservation of a functional ZAC in mammals was probed by investigating the abilities of a selection of ZACs from 10 other mammalian species than human to be expressed at the protein level and assemble into cell surface-expressed functional receptors in mammalian cells and in Xenopus oocytes. In an enzyme-linked immunosorbent assay, transient transfections of tsA201 cells with cDNAs of hemagglutinin (HA)-epitope-tagged versions of these 10 ZACs resulted in robust total expression and cell surface expression levels of all proteins. Moreover, injection of cRNAs for 6 of these ZACs in oocytes resulted in the formation of functional receptors in two-electrode voltage-clamp recordings. The ZACs exhibited robust current amplitudes in response to Zn2+ (10 mM) and H+ (pH 4.0), and the concentration-response relationships displayed by Zn2+ at these channels were largely comparable to that at human ZAC. In conclusion, the findings suggest that the functionality of ZAC at the molecular level may be conserved throughout mammalian species, and that the channel thus may govern physiological functions in mammals, including humans.

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Section: Functional Properties Displayed By 7 Mammalian Zacs In Xenop...supporting

confidence: 92%

Evolutionary conservation of Zinc-Activated Channel (ZAC) functionality in mammals: a range of mammalian ZACs assemble into cell surface-expressed functional receptors

Jensen

2023

Front. Mol. Biosci.

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Probing the molecular basis for signal transduction through the Zinc-Activated Channel (ZAC)

Madjroh

Mellou

Æbelø

et al. 2021

Biochemical Pharmacology

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Discovery and functional characterization of N-(thiazol-2-yl)-benzamide analogs as the first class of selective antagonists of the Zinc-Activated Channel (ZAC)

Cited by 2 publications

References 58 publications

Evolutionary conservation of Zinc-Activated Channel (ZAC) functionality in mammals: a range of mammalian ZACs assemble into cell surface-expressed functional receptors

Evolutionary conservation of Zinc-Activated Channel (ZAC) functionality in mammals: a range of mammalian ZACs assemble into cell surface-expressed functional receptors

Probing the molecular basis for signal transduction through the Zinc-Activated Channel (ZAC)

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