Functional analysis in a model sea anemone reveals phylogenetic complexity and a role in cnidocyte discharge of DEG/ENaC ion channels

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: Jan. 6, 2023

Ion channels of the DEG/ENaC family share a similar structure but serve strikingly diverse biological functions, such as Na

Language: Английский

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Structural basis for excitatory neuropeptide signaling

Nature Structural & Molecular Biology, Journal Year: 2024, Volume and Issue: 31(4), P. 717 - 726

Published: Feb. 9, 2024

Rapid signaling between neurons is mediated by ligand-gated ion channels, cell-surface proteins with an extracellular ligand-binding domain and a membrane-spanning channel domain. The degenerin/epithelial sodium (DEG/ENaC) superfamily diverse in terms of its gating stimuli, some DEG/ENaCs gated neuropeptides, others pH, mechanical force or enzymatic activity. mechanism which ligands bind to activate poorly understood. Here we dissected the structural basis for neuropeptide-gated activity DEG/ENaC, FMRFamide-gated 1 (FaNaC1) from annelid worm Malacoceros fuliginosus, using cryo-electron microscopy. Structures FaNaC1 ligand-free resting state several ligand-bound states reveal site capture ligand-induced conformational changes gating, verified complementary mutagenesis experiments. Our results illuminate offer template experimental dissection pharmacology conduction.

Language: Английский

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Comparative analysis defines a broader FMRFamide-gated sodium channel family and determinants of neuropeptide sensitivity

Journal of Biological Chemistry, Journal Year: 2022, Volume and Issue: 298(7), P. 102086 - 102086

Published: May 27, 2022

FMRFamide (Phe-Met-Arg-Phe-amide, FMRFa) and similar neuropeptides are important physiological modulators in most invertebrates, but the molecular basis of FMRFa activity at its receptors is unknown. We therefore sought to identify determinants potency against one native targets, excitatory FMRFa-gated sodium channel (FaNaC) from gastropod mollusks. Using phylogenetics electrophysiological measurement neuropeptide activity, we identified a broad FaNaC family that includes mollusk annelid channels gated by FMRFa, FVRIamides, and/or Wamides (or myoinhibitory peptides). A comparative analysis this broader other overarching degenerin (DEG)/epithelial (ENaC) superfamily, incorporating mutagenesis experimental dissection function, pocket amino acid residues determines activation FaNaCs neuropeptides. Although has diverged distantly related DEG/ENaC activated ligands enhanced such as mammalian acid-sensing ion channels, show it nonetheless contains determine enhancement those peptides. This study thus identifies receptor illuminates evolution ligand recognition branch superfamily channels.

Language: Английский

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Function and phylogeny support the independent evolution of an ASIC-like Deg/ENaC channel in the Placozoa

Communications Biology, Journal Year: 2023, Volume and Issue: 6(1)

Published: Sept. 18, 2023

ASIC channels are bilaterian proton-gated sodium belonging to the large and functionally-diverse Deg/ENaC family that also includes peptide- mechanically-gated channels. Here, we report non-bilaterian invertebrate Trichoplax adhaerens possesses a proton-activated channel, TadNaC2, with unique combination of biophysical features including tachyphylaxis like ASIC1a, reduced proton sensitivity ASIC2a, biphasic macroscopic currents ASIC3, as well low channel blocker amiloride Ca2+ ions. Structural modeling mutation analyses reveal TadNaC2 gating is different from channels, lacking key molecular determinants, involving residues within palm finger regions. Phylogenetic analysis reveals monophyletic clade T. which phylogenetically distinct instead forming BASIC Altogether, this work suggests ASIC-like evolved independently in its phylum Placozoa. Our phylogenetic identifies several clades uncharacterized metazoan provides evidence for existence outside Metazoa, present gene data select unicellular heterokont filasterea-related species.

Language: Английский

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Digestive System Development and Posterior Hox/Parahox Gene Expression During Larval Life and Metamorphosis of the Phoronid Phoronopsis harmeri

Journal of Experimental Zoology Part B Molecular and Developmental Evolution, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

ABSTRACT Phoronida is a small group of marine animals, most which are characterized by long larval period and complex metamorphosis. As result metamorphosis, their body changes so much that true anterior posterior ends very close to each other, the intestine becomes U‐shaped. Using histology electron microscopy, we have shown elongation change in shape digestive tract occurs during metamorphosis Phoronopsis harmeri larvae accompanied formation new parts ultrastructure. At same time, our situ hybridization data suggest markers Cdx Post2 expressed tissues at stages, juveniles, expression correlate with remodeling tract. Our may shed light on evolution patterning animals undergoing

Language: Английский

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Invertebrate Bile Acid‐Sensitive Ion Channels and Their Emergence in Bilateria

The FASEB Journal, Journal Year: 2025, Volume and Issue: 39(8)

Published: April 16, 2025

ABSTRACT The broad Degenerin/epithelial sodium channel (DEG/ENaC) family includes a subfamily of bile acid‐sensing ion channels (BASICs). While their biophysical properties are extensively studied in mammals, the presence and function BASICs invertebrates remain largely unexplored. Here, we present first functional evidence invertebrate BASICs, revealing conserved features evolutionary adaptations across bilaterian species. Using electrophysiological pharmacological approaches, show that exhibit species‐specific acid sensitivity profiles differing responses to blockers, amiloride, diminazene, while retaining shared like inhibition by calcium ions selective permeability ions. For example, acorn worm Schizocardium californicum BASIC displays similar brachiopod Novocrania anomala is activated solely ursodeoxycholic (UDCA) our experiments. Mutagenesis D444 residue pore‐lining region confirms its critical role gating. Combined phylogenetic analysis suggests emerged early evolution, evolving from were merely modulated acids, cousins, into acids. Tissue‐specific expression patterns imply roles acid‐dependent absorption or environmental sensing acid‐like compounds. Given absence endogenous acids invertebrates, propose may detect compounds, contributing ecological interactions. This study enhances understanding evolutionary, functional, with implications for future research native ligands.

Language: Английский

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The complete catalog of antimicrobial resistance secondary active transporters in C. difficile: evolution and drug resistance perspective

Computational and Structural Biotechnology Journal, Journal Year: 2024, Volume and Issue: 23, P. 2358 - 2374

Published: May 21, 2024

Secondary active transporters shuttle substrates across eukaryotic and prokaryotic membranes, utilizing different electrochemical gradients. They are recognized as one of the antimicrobial efflux pumps among pathogens. While primary within genome C. difficile 630 have been completely cataloged, systematical study secondary remains incomplete. Here, we not only identify but also disclose their evolution role in drug resistance 630. Our analysis reveals that carries 147 belonging to 27 (super)families. Notably, 50 (34%) them potentially contribute (AMR). AMR-secondary structurally classified into five (super)families: p-aminobenzoyl-glutamate transporter (AbgT), drug/metabolite (DMT) superfamily, major facilitator (MFS) multidrug toxic compound extrusion (MATE) family, resistance-nodulation-division (RND) family. Surprisingly, complete RND genes found likely an evolutionary leftover from common ancestor with diderm. Through protein structure comparisons, identified six novel DMT, MATE, MFS Pangenome revealed half accessory genes, which indicates important adaptive AMR function rather than innate physiological homeostasis. Gene expression profile firmly supports ability respond a wide spectrum antibiotics. findings highlight integral antibiotic responses. This marks interesting therapeutic targets synergize other activity.

Language: Английский

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A conserved peptide-binding pocket in HyNaC/ASIC ion channels

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(41)

Published: Oct. 4, 2024

The only known peptide-gated ion channels—FaNaCs/WaNaCs and HyNaCs—belong to different clades of the DEG/ENaC family. FaNaCs are activated by short neuropeptide FMRFamide, HyNaCs Hydra RFamides, which not evolutionarily related FMRFamide. FMRFamide-binding site in was recently identified a cleft atop large extracellular domain. However, this is conserved HyNaCs. Here, we combined molecular modeling site-directed mutagenesis putative binding pocket for Hydra-RFamides domain heterotrimeric HyNaC2/3/5. This localizes one three subunit interfaces, indicating that trimeric channel binds single peptide ligand. We engineered an unnatural amino acid at entrance, allowed covalent tethering RFamide channel, thereby trapping open conformation. same region as acidic acid-sensing channels (ASICs), ligands. less acidic, both electrostatic hydrophobic interactions contribute binding. Collectively, our results reveal ligand-binding ASICs indicate independent evolution peptide-binding cavities two subgroups channels.

Language: Английский

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The diverse functions of the DEG/ENaC family: linking genetic and physiological insights

The Journal of Physiology, Journal Year: 2022, Volume and Issue: 601(9), P. 1521 - 1542

Published: Oct. 31, 2022

The DEG/ENaC family of ion channels was defined based on the sequence similarity between degenerins (DEG) from nematode Caenorhabditis elegans and subunits mammalian epithelial sodium channel (ENaC), also includes a diverse array non-voltage-gated cation across animal phyla, including acid-sensing (ASICs) Drosophila pickpockets. ENaCs ASICs have wide ranging medical importance; for example, play an important role in respiratory renal function, ischaemia inflammatory pain, as well being implicated memory learning. Electrophysiological approaches, both vitro vivo, played essential establishing physiological properties this family, identifying modulators implicating them extensive range cellular functions, mechanosensation, acid sensation synaptic modulation. Likewise, genetic studies invertebrates vertebrates linking our understanding to function at whole animal/behavioural level. Drawing together evidence is furthering precise roles channels, with diversity among members allowing comparative dissect molecular basis these functions.

Language: Английский

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Ion channels in macrophages: Implications for disease progression

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 144, P. 113628 - 113628

Published: Nov. 19, 2024

Language: Английский

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