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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.
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