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PLoS One
2019 Jan 01;141:e0210182. doi: 10.1371/journal.pone.0210182.
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Curare alkaloids from Matis Dart Poison: Comparison with d-tubocurarine in interactions with nicotinic, 5-HT3 serotonin and GABAA receptors.
Spirova EN
,
Ivanov IA
,
Kasheverov IE
,
Kudryavtsev DS
,
Shelukhina IV
,
Garifulina AI
,
Son LV
,
Lummis SCR
,
Malca-Garcia GR
,
Bussmann RW
,
Hennig L
,
Giannis A
,
Tsetlin VI
.
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Several novel bisbenzylisoquinoline alkaloids (BBIQAs) have recently been isolated from a Matis tribe arrow poison and shown by two-electrode voltage-clamp to inhibit mouse muscle nicotinic acetylcholine receptors (nAChR). Here, using radioligand assay with Aplysia californica AChBP and radioiodinated α-bungarotoxin ([125I]-αBgt), we show that BBIQA1, BBIQA2, and d-tubocurarine (d-TC) have similar affinities to nAChR orthosteric site. However, a competition with [125I]-αBgt for binding to the Torpedo californica muscle-type nAChR revealed that BBIQAs1, 2, and 3 are less potent (IC50s = 26.3, 8.75, and 17.0 μM) than d-TC (IC50 = 0.39 μM), while with α7 nAChR in GH4C1 cells, BBIQA1 was less potent that d-TC (IC50s = 162 μM and 7.77 μM, respectively), but BBIQA2 was similar (IC50 = 5.52 μM). In inhibiting the Ca2+ responses induced by acetylcholine in Neuro2a cells expressing the mouse adult α1β1εδ nAChR or human α7 nAChR, BBIQAs1 and 2 had similar potencies to d-TC (IC50s in the range 0.75-3.08 μM). Our data suggest that BBIQA1 and BBIQA2 can inhibit adult muscle α1β1εδ nAChR by both competitive and noncompetitive mechanisms. Further experiments on neuronal α3β2, α4β2, and α9α10 nAChRs, expressed in Xenopus laevis oocytes, showed that similar potencies for BBIQAs1, 2, and d-TC. With α3β2γ2 GABAAR currents were almost completely inhibited by d-TC at a high (100 μM) concentration, but BBIQAs1 and 2 were less potent (only 40-50% inhibition), whereas in competition with Alexa Fluor 546-α-cobratoxin for binding to α1β3γ2 GABAAR in Neuro2a cells, d-TC and these analogs had comparable affinities. Especially interesting effects of BBIQAs1 and 2 in comparison with d-TC were observed for 5-HT3AR: BBIQA1 and BBIQA2 were 5- and 87-fold less potent than d-TC (IC50 = 22.63 nM). Thus, our results reveal that these BBIQAs differ from d-TC in their potencies towards certain Cys-loop receptors, and we suggest that understanding the reasons behind this might be useful for future drug design.
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Fig 1. Chemical structures of d-tubocurarine (d-TC) and bisbenzyltetrahydroisoquinoline alkaloids (BBIQAs).
Fig 2. Inhibition of [125I]-labeled α-bungarotoxin binding.(a) to A. californica AChBP, (b) to nAChR from Torpedo californica electric organ membranes, and (c) to human α7 nAChR in GH4C1 cells with BBIQA1 (open blue triangles), BBIQA2 (open red squares), BBIQA3 (open green rhombuses), and d-TC (open black circles). Data are mean ± SEM of two biological replicates with duplicates for each point (the number of technical replicates is 2), i.e. n = 4. IC50 values derived from these data are shown in Table 1.
Fig 3. Dose-response curves of inhibitory activity of d-TC (open black circles), BBIQA1 (open blue triangles), and BBIQA2 (open red squares).(a) on the 30 μM (approx. EC50) acetylcholine-evoked intracellular calcium ion concentration ([Ca2+]i) rise in Neuro2a cells expressing mouse adult α1β1εδ nAChRs; and (b) on the 10 μM (approx. EC50) acetylcholine-evoked [Ca2+]i rise in Neuro2a cells expressing human α7 nAChRs in the presence of 10 μM PNU120596. Data are presented as mean ± SEM, n = 3. The respective IC50 values are shown in the Table 1. (c) Dose-response curves of acetylcholine (ACh)-evoked [Ca2+]i rise in the absence (grey circles, EC50 = 8.4 ± 0.6 μM) and presence of d-TC (black circles) or its analogs, BBIQA1 (blue triangles), and BBIQA2 (red squares) at different concentrations in Neuro2a cells expressing mouse adult α1β1εδ nAChRs. Data are presented as mean ± SEM, n = 3. EC50 values are shown in the Table 2.
Fig 4. Activity of d-TC, BBIQAs1 and 2 against heteromeric neuronal nAChRs, GABAAR, and 5-HT3AR.(a) Representative current traces of human α3β2 nAChR, showing inhibition of nicotine (50 μM)-induced current by 10 μM d-TC, BBIQA1, or BBIQA2. (b) Bar graph for d-TC and BBIQAs (1 and 10 μM) inhibition of agonist-evoked currents mediated by human α3β2 (50 μM Nicotine), rat α4β2 (10 μM Nicotine), and human α9α10 (25 μM Acetylcholine) nAChRs. (c) Bar graph for d-TC and BBIQAs (100 μM) inhibition of agonist-evoked currents mediated by mouse α3β2γ2 GABAAR (100 μM GABA). (d) Inhibition of Alexa Fluor 546 α-cobratoxin (αCtx, 50 nM) binding to α1β3γ2 GABAAR expressed in Neuro2a cells by 50 μM d-TC, BBIQAs 1 and 2. The bar graph represents the remaining fluorescence of Alexa Fluor 546 αCtx (50 nM). In (a, b, c, d) data are presented as mean ± SEM, n = 3–6. One-way ANOVA with Tukey’s HSD test, (black asterisks, p<0.05, normalized current evoked by agonist in the presence of d-TC, BBIQA1, or BBIQA2 vs normalized current induced by agonist in the absence of antagonists). (e) Dose-response curves of d-TC (open black circles), BBIQA1 (open blue triangles), or BBIQA2 (open red squares) inhibitory action on 1 μM 5-HT-evoked ion currents mediated by mouse 5-HT3AR. Data are presented as mean ± SEM, n = 3–5. IC50 values determined from these data are shown in Table 1.
Bertrand,
The wonderland of neuronal nicotinic acetylcholine receptors.
2018, Pubmed
Bertrand,
The wonderland of neuronal nicotinic acetylcholine receptors.
2018,
Pubmed
Bertrand,
Allosteric modulation of nicotinic acetylcholine receptors.
2007,
Pubmed
Bouzat,
The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization.
2008,
Pubmed
Bowman,
Structure:action relationships among some desacetoxy analogues of pancuronium and vecuronium in the anesthetized cat.
1988,
Pubmed
Bowman,
Neuromuscular block.
2006,
Pubmed
Brams,
A structural and mutagenic blueprint for molecular recognition of strychnine and d-tubocurarine by different cys-loop receptors.
2011,
Pubmed
Braun,
Gamma-aminobutyric acid (GABA) is an autocrine excitatory transmitter in human pancreatic beta-cells.
2010,
Pubmed
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Burgos,
Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors.
2016,
Pubmed
Chatzidaki,
The influence of allosteric modulators and transmembrane mutations on desensitisation and activation of α7 nicotinic acetylcholine receptors.
2015,
Pubmed
,
Xenbase
Chua,
GABAA Receptors and the Diversity in their Structure and Pharmacology.
2017,
Pubmed
Dani,
Neuronal Nicotinic Acetylcholine Receptor Structure and Function and Response to Nicotine.
2015,
Pubmed
Dickinson,
Differential coupling of alpha7 and non-alpha7 nicotinic acetylcholine receptors to calcium-induced calcium release and voltage-operated calcium channels in PC12 cells.
2007,
Pubmed
Dineley,
Nicotinic ACh receptors as therapeutic targets in CNS disorders.
2015,
Pubmed
Foucault-Fruchard,
Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases.
2017,
Pubmed
Gahring,
Nicotinic alpha 7 receptor expression and modulation of the lung epithelial response to lipopolysaccharide.
2017,
Pubmed
Gill,
Contrasting properties of α7-selective orthosteric and allosteric agonists examined on native nicotinic acetylcholine receptors.
2013,
Pubmed
Groot-Kormelink,
High Throughput Random Mutagenesis and Single Molecule Real Time Sequencing of the Muscle Nicotinic Acetylcholine Receptor.
2016,
Pubmed
Hassaine,
X-ray structure of the mouse serotonin 5-HT3 receptor.
2014,
Pubmed
Heier,
[Muscle relaxants].
2010,
Pubmed
Hone,
α9-containing nicotinic acetylcholine receptors and the modulation of pain.
2018,
Pubmed
Huang,
Complex between α-bungarotoxin and an α7 nicotinic receptor ligand-binding domain chimaera.
2013,
Pubmed
Hurst,
A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization.
2005,
Pubmed
,
Xenbase
Inserra,
Isolation and characterization of α-conotoxin LsIA with potent activity at nicotinic acetylcholine receptors.
2013,
Pubmed
Jonsson,
Distinct pharmacologic properties of neuromuscular blocking agents on human neuronal nicotinic acetylcholine receptors: a possible explanation for the train-of-four fade.
2006,
Pubmed
,
Xenbase
Jonsson Fagerlund,
Pharmacological characteristics of the inhibition of nondepolarizing neuromuscular blocking agents at human adult muscle nicotinic acetylcholine receptor.
2009,
Pubmed
,
Xenbase
Karpen,
Acetylcholine receptor inhibition by d-tubocurarine involves both a competitive and a noncompetitive binding site as determined by stopped-flow measurements of receptor-controlled ion flux in membrane vesicles.
1986,
Pubmed
Kawashima,
Critical roles of acetylcholine and the muscarinic and nicotinic acetylcholine receptors in the regulation of immune function.
2012,
Pubmed
Kudryavtsev,
Marine natural products acting on the acetylcholine-binding protein and nicotinic receptors: from computer modeling to binding studies and electrophysiology.
2014,
Pubmed
,
Xenbase
Kudryavtsev,
Neurotoxins from snake venoms and α-conotoxin ImI inhibit functionally active ionotropic γ-aminobutyric acid (GABA) receptors.
2015,
Pubmed
,
Xenbase
Lemoine,
Ligand-gated ion channels: new insights into neurological disorders and ligand recognition.
2012,
Pubmed
Lien,
Development and potential clinical impairment of ultra-short-acting neuromuscular blocking agents.
2011,
Pubmed
Malca Garcia,
Curare Alkaloids: Constituents of a Matis Dart Poison.
2015,
Pubmed
,
Xenbase
Matsuda,
Serotonin regulates mammary gland development via an autocrine-paracrine loop.
2004,
Pubmed
Meakin,
Recent advances in myorelaxant therapy.
2001,
Pubmed
Morales-Perez,
X-ray structure of the human α4β2 nicotinic receptor.
2016,
Pubmed
Morris,
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility.
2009,
Pubmed
Murebwayire,
Triclisia sacleuxii (Pierre) Diels (Menispermaceae), a potential source of acetylcholinesterase inhibitors.
2009,
Pubmed
Nys,
Structural insights into Cys-loop receptor function and ligand recognition.
2013,
Pubmed
Paul,
Antiemetics of the 5-hydroxytryptamine 3A antagonist class inhibit muscle nicotinic acetylcholine receptors.
2005,
Pubmed
,
Xenbase
Pettersen,
UCSF Chimera--a visualization system for exploratory research and analysis.
2004,
Pubmed
Roncarati,
Functional properties of alpha7 nicotinic acetylcholine receptors co-expressed with RIC-3 in a stable recombinant CHO-K1 cell line.
2008,
Pubmed
Savarese,
Does clinical anesthesia need new neuromuscular blocking agents?
1975,
Pubmed
Semwal,
From arrow poison to herbal medicine--the ethnobotanical, phytochemical and pharmacological significance of Cissampelos (Menispermaceae).
2014,
Pubmed
Shelukhina,
Calcium imaging with genetically encoded sensor Case12: Facile analysis of α7/α9 nAChR mutants.
2017,
Pubmed
Sine,
End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease.
2012,
Pubmed
Spurny,
Pentameric ligand-gated ion channel ELIC is activated by GABA and modulated by benzodiazepines.
2012,
Pubmed
,
Xenbase
Spurny,
Molecular blueprint of allosteric binding sites in a homologue of the agonist-binding domain of the α7 nicotinic acetylcholine receptor.
2015,
Pubmed
,
Xenbase
Szabo,
Mode of action of the positive modulator PNU-120596 on α7 nicotinic acetylcholine receptors.
2014,
Pubmed
Thompson,
The 5-HT3 receptor as a therapeutic target.
2007,
Pubmed
Tuba,
Synthesis and structure-activity relationships of neuromuscular blocking agents.
2002,
Pubmed
Vemparala,
Computational studies on the interactions of inhalational anesthetics with proteins.
2010,
Pubmed
Vulfius,
Peptides from puff adder Bitis arietans venom, novel inhibitors of nicotinic acetylcholine receptors.
2016,
Pubmed
,
Xenbase
Wang,
Curariform antagonists bind in different orientations to the nicotinic receptor ligand binding domain.
2003,
Pubmed
Williams,
Positive allosteric modulators as an approach to nicotinic acetylcholine receptor-targeted therapeutics: advantages and limitations.
2011,
Pubmed
Wintersteiner,
CURARE ALKALOIDS FROM CHONDODENDRON TOMENTOSUM.
1943,
Pubmed
Wotring,
The inhibitory effects of nicotinic antagonists on currents elicited by GABA in rat hippocampal neurons.
1995,
Pubmed
Wu,
Ion channels gated by acetylcholine and serotonin: structures, biology, and drug discovery.
2015,
Pubmed
Yamauchi,
Characterizing ligand-gated ion channel receptors with genetically encoded Ca2++ sensors.
2011,
Pubmed
Young,
Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site.
2008,
Pubmed
,
Xenbase
Zhang,
The role of loop F residues in determining differential d-tubocurarine potencies in mouse and human 5-hydroxytryptamine 3A receptors.
2007,
Pubmed
,
Xenbase
Zoli,
Neuronal and Extraneuronal Nicotinic Acetylcholine Receptors.
2018,
Pubmed
daCosta,
Stoichiometry for α-bungarotoxin block of α7 acetylcholine receptors.
2015,
Pubmed