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

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

doi:10.1016/j.bcp.2021.114781

Cited by 9 publications

(12 citation statements)

References 80 publications

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“…Another, sometimes termed atypical, member of the cys-loop receptor superfamily is the zinc-activated channel (ZAC) ( Davies et al, 2003 ). ZAC is directly gated by the ions Zn 2+ , Cu 2+ and H + , a property that seems to be unique among mammalian cys-loop receptors ( Trattnig et al, 2016 ; Madjroh et al, 2021 ). Additionally, ZAC has distinct gating characteristics as seen with homomeric ZACs expressed in heterologous systems, such as considerable spontaneous activity, and slow activation and desensitization kinetics ( Madjroh et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…ZAC is directly gated by the ions Zn 2+ , Cu 2+ and H + , a property that seems to be unique among mammalian cys-loop receptors ( Trattnig et al, 2016 ; Madjroh et al, 2021 ). Additionally, ZAC has distinct gating characteristics as seen with homomeric ZACs expressed in heterologous systems, such as considerable spontaneous activity, and slow activation and desensitization kinetics ( Madjroh et al, 2021 ). However, little is known about the physiological role of this receptor.…”

Section: Introductionmentioning

confidence: 99%

“…However, little is known about the physiological role of this receptor. It has low amino acid sequence homology with the other members of the superfamily, but contains most of the major structural elements of a cys-loop receptor subunit ( Madjroh et al, 2021 ). ZAC is expressed in several organs, such as pancreas, placenta, prostate, thyroid, as well as the adult and fetal brain ( Davies et al, 2003 ; Houtani et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

“…ZAC is expressed in several organs, such as pancreas, placenta, prostate, thyroid, as well as the adult and fetal brain ( Davies et al, 2003 ; Houtani et al, 2005 ). The exploration of pharmacological tools to specifically target ZAC has proven to be challenging due to off-target action of several allosteric modulators in other cys-loop receptors ( Madjroh et al, 2021 ), thus it is likely also an unknown player in adverse events elicited by pLGIC targeting substances.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

Koniuszewski

Vogel

Bampali

et al. 2022

Front. Mol. Biosci.

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Background: Human pentameric ligand-gated ion channels (pLGICs) comprise nicotinic acetylcholine receptors (nAChRs), 5-hydroxytryptamine type 3 receptors (5-HT3Rs), zinc-activated channels (ZAC), γ-aminobutyric acid type A receptors (GABAARs) and glycine receptors (GlyRs). They are recognized therapeutic targets of some of the most prescribed drugs like general anesthetics, anxiolytics, smoking cessation aids, antiemetics and many more. Currently, approximately 100 experimental structures of pLGICs with ligands bound exist in the protein data bank (PDB). These atomic-level 3D structures enable the generation of a comprehensive binding site inventory for the superfamily and the in silico prediction of binding site properties.Methods: A panel of high throughput in silico methods including pharmacophore screening, conformation analysis and descriptor calculation was applied to a selection of allosteric binding sites for which in vitro screens are lacking. Variant abundance near binding site forming regions and computational docking complement the approach.Results: The structural data reflects known and novel binding sites, some of which may be unique to individual receptors, while others are broadly conserved. The membrane spanning domain, comprising four highly conserved segments, contains ligand interaction sites for which in vitro assays suitable for high throughput screenings are critically lacking. This is also the case for structurally more variable novel sites in the extracellular domain. Our computational results suggest that the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC) can utilize multiple pockets which are likely to exist on most superfamily members.Conclusion: With this study, we explore the potential for polypharmacology among pLGICs. Our data suggest that ligands can display two forms of promiscuity to an extent greater than what has been realized: 1) Ligands can interact with homologous sites in many members of the superfamily, which bears toxicological relevance. 2) Multiple pockets in distinct localizations of individual receptor subtypes share common ligands, which counteracts efforts to develop selective agents. Moreover, conformational states need to be considered for in silico drug screening, as certain binding sites display considerable flexibility. In total, this work contributes to a better understanding of polypharmacology across pLGICs and provides a basis for improved structure guided in silico drug development and drug derisking.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

Koniuszewski

Vogel

Bampali

et al. 2022

Front. Mol. Biosci.

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“…The excitatory cation-selective pLGICs respond to the neurotransmitters, acetylcholine (nicotinic acetylcholine receptor, nAChR) and serotonin (serotonin receptor, 5-HT 3 R), while the inhibitory anion-selective pLGICs respond to γ-aminobutyric acid (GABA receptor, GABA A R) and glycine (glycine receptor, GlyR). Humans also uniquely express a cation-selective zinc-activated channel, ZAC [ 14 ]. Each of the four main families includes a variety of functional hetero- and homo-pentamers that form from different combinations of the sixteen distinct nAChR subunits (α1–α7, α9–α10, β1–β4, δ, γ, and ε), the five distinct 5-HT 3 AR subunits (A–E), the nineteen distinct GABA A R subunits (α1–α6, β1–β3,γ1–γ3, ε, δ, π, θ, and ρ1–ρ3) or the five distinct GlyR subunits (α1–α4, and β).…”

Section: Introductionmentioning

confidence: 99%

Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

et al. 2022

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Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function and may help shape synaptic communication. Increasing structural and biophysical data reveal sites for lipid binding to pLGICs. Here, we update our evolving understanding of pLGIC–lipid interactions highlighting newly identified modes of lipid binding along with the mechanistic understanding derived from the new structural data.

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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)

Madjroh

Mellou

Davies

et al. 2021

Biochemical Pharmacology

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

Cited by 9 publications

References 80 publications

Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

Molecular Mingling: Multimodal Predictions of Ligand Promiscuity in Pentameric Ligand-Gated Ion Channels

Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

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

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