马提斯箭毒中的箭毒堿：与 d-筒箭毒堿与烟碱型、5-HT3 血清素和 GABAA 受体相互作用的比较。
Curare alkaloids from Matis Dart Poison: Comparison with d-tubocurarine in interactions with nicotinic, 5-HT3 serotonin and GABAA receptors.
机构信息
Department of Molecular Neuroimmune signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
Sechenov First Moscow State Medical University, Institute of Molecular Medicine, Moscow, Russia.
出版信息
PLoS One. 2019 Jan 4;14(1):e0210182. doi: 10.1371/journal.pone.0210182. eCollection 2019.
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.
几种新型双苄基异喹啉生物碱（BBIQAs）最近从马蒂斯部落的箭毒中分离出来，并通过双电极电压钳实验证明可抑制小鼠肌肉烟碱型乙酰胆碱受体（nAChR）。在这里，我们使用加利福尼亚海兔乙酰胆碱结合蛋白（Aplysia californica AChBP）和放射性碘标记的α-银环蛇毒素（[125I]-αBgt）进行放射性配体测定，结果表明 BBIQA1、BBIQA2 和 d-筒箭毒碱（d-TC）对 nAChR 变构位点具有相似的亲和力。然而，[125I]-αBgt 与 Torpedo californica 肌肉型 nAChR 的结合竞争表明，BBIQAs1、2 和 3 的效力比 d-TC（IC50 = 0.39 μM）低（IC50s = 26.3、8.75 和 17.0 μM），而与 GH4C1 细胞中的 α7 nAChR 相比，BBIQA1 的效力比 d-TC 低（IC50s 分别为 162 μM 和 7.77 μM），但 BBIQA2 相似（IC50 = 5.52 μM）。在抑制表达小鼠成年 α1β1εδ nAChR 或人 α7 nAChR 的 Neuro2a 细胞中乙酰胆碱诱导的 Ca2+反应时，BBIQAs1 和 2 与 d-TC 具有相似的效力（IC50 在 0.75-3.08 μM 范围内）。我们的数据表明，BBIQA1 和 BBIQA2 可以通过竞争性和非竞争性机制抑制成人肌肉 α1β1εδ nAChR。在非洲爪蟾卵母细胞中表达神经元 α3β2、α4β2 和 α9α10 nAChR 的进一步实验表明，BBIQAs1、2 和 d-TC 的效力相似。对于 α3β2γ2 GABAAR 电流，d-TC 在高浓度（100 μM）下几乎完全抑制，但 BBIQAs1 和 2 的效力较低（仅抑制 40-50%），而在与 Alexa Fluor 546-α-cobratoxin 竞争结合 Neuro2a 细胞中的 α1β3γ2 GABAAR 时，d-TC 和这些类似物具有可比的亲和力。与 d-TC 相比，BBIQAs1 和 2 对 5-HT3AR 的有趣影响尤其明显：BBIQA1 和 BBIQA2 的效力比 d-TC 低 5 倍和 87 倍（IC50 = 22.63 nM）。因此，我们的结果表明，这些 BBIQAs 在它们对某些 Cys-环受体的效力方面与 d-TC 不同，我们建议，了解背后的原因可能对未来的药物设计有用。
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