A potential cost of evolving epibatidine resistance in poison frogs.
A potential cost of evolving epibatidine resistance in poison frogs.
复制标题
DOI：
10.1186/s12915-023-01637-8
复制
发表时间：
2023-06-28
期刊：
影响因子：
5.4
通讯作者：
Zakon, Harold H.
中科院分区：
文献类型：
--
作者：
York, Julia M.;Borghese, Cecilia M.;George, Andrew A.;Cannatella, David C.;Zakon, Harold H.
关键词：
一些树突类毒蛙会将毒素表巴替丁隔离起来，以此来防御捕食者。我们之前在树蛙的烟碱型乙酰胆碱受体β2亚单位的一个高度保守的位置发现了一个氨基酸替换(S108C)，它降低了脑中表达α4β2受体对表巴替丁的敏感性。将S108C引入同源高敏感性人类受体类似地降低了对表巴替丁的敏感性，但也降低了对乙酰胆碱的敏感性，如果这种情况发生在树突动物身上，这将是一个潜在的成本。乙酰胆碱敏感性的下降表现为与低敏感性受体的添加相一致的两相乙酰胆碱浓度-反应曲线。令人惊讶的是，将β2 S108C添加到树突幼虫的α4β2受体中并没有改变乙酰胆碱的敏感性，似乎是免费的。我们提出，携带毒素的树枝状动物可能有额外的氨基酸取代，以保护其受体免受乙酰胆碱敏感性变化的影响。为了验证这一点，在目前的研究中，我们比较了Dendrobatid受体及其来自两种非Dendrobatid青蛙的同源物。将S108C引入两种非树突蛙的α4β2受体中也不影响乙酰胆碱的敏感性，这表明没有额外的树突特异性替代。然而，S108C降低了附足蛙和非树突蛙神经递质诱导的电流的幅度。我们使用针对受体的放射性标记抗体证实，在附足类动物中，电流的减少是由于质膜上的受体较少所致。为了测试S108C改变人受体对乙酰胆碱的敏感性是由于(1)通过改变化学计量比增加了低敏感性结合位点，还是(2)在不改变化学计量比的情况下将现有的高敏感性结合位点转换为低敏感性结合位点，我们在化学计量学中制作了串联的α-4-β-2受体。S108C取代减少了免疫标记受体的最大电流和数量，但不再改变乙酰胆碱的敏感性。对我们目前和以前工作最简明的解释是，S108C取代使β2亚单位在组装/运输方面的效率降低，从而减少了质膜上的受体数量。因此，虽然β2 S108C保护树枝状虫不受隔离的表巴替丁的影响，但它引起了潜在的生理代价，即α4β2受体功能中断。网上版载有补充材料，可在10.1186/s12915-023-01637-8查阅。
Some dendrobatid poison frogs sequester the toxin epibatidine as a defense against predators. We previously identified an amino acid substitution (S108C) at a highly conserved site in a nicotinic acetylcholine receptor β2 subunit of dendrobatid frogs that decreases sensitivity to epibatidine in the brain-expressing α4β2 receptor. Introduction of S108C to the orthologous high-sensitivity human receptor similarly decreased sensitivity to epibatidine but also decreased sensitivity to acetylcholine, a potential cost if this were to occur in dendrobatids. This decrease in the acetylcholine sensitivity manifested as a biphasic acetylcholine concentration–response curve consistent with the addition of low-sensitivity receptors. Surprisingly, the addition of the β2 S108C into the α4β2 receptor of the dendrobatid Epipedobates anthonyi did not change acetylcholine sensitivity, appearing cost-free. We proposed that toxin-bearing dendrobatids may have additional amino acid substitutions protecting their receptors from alterations in acetylcholine sensitivity. To test this, in the current study, we compared the dendrobatid receptor to its homologs from two non-dendrobatid frogs. The introduction of S108C into the α4β2 receptors of two non-dendrobatid frogs also does not affect acetylcholine sensitivity suggesting no additional dendrobatid-specific substitutions. However, S108C decreased the magnitude of neurotransmitter-induced currents in Epipedobates and the non-dendrobatid frogs. We confirmed that decreased current resulted from fewer receptors in the plasma membrane in Epipedobates using radiolabeled antibodies against the receptors. To test whether S108C alteration of acetylcholine sensitivity in the human receptor was due to (1) adding low-sensitivity binding sites by changing stoichiometry or (2) converting existing high- to low-sensitivity binding sites with no stoichiometric alteration, we made concatenated α4β2 receptors in stoichiometry with only high-sensitivity sites. S108C substitutions decreased maximal current and number of immunolabeled receptors but no longer altered acetylcholine sensitivity. The most parsimonious explanation of our current and previous work is that the S108C substitution renders the β2 subunit less efficient in assembling/trafficking, thereby decreasing the number of receptors in the plasma membrane. Thus, while β2 S108C protects dendrobatids against sequestered epibatidine, it incurs a potential physiological cost of disrupted α4β2 receptor function. The online version contains supplementary material available at 10.1186/s12915-023-01637-8.
登录
查看更多内容
影响因子：
4.7
作者：
Dash B;Bhakta M;Chang Y;Lukas RJ
通讯作者：
Lukas RJ
影响因子：
7.4
作者：
Fu, Xu;Moonschi, Faruk H.;Richards, Christopher I.
通讯作者：
Richards, Christopher I.
影响因子：
3.6
作者：
Kuryatov, Alexandre;Lindstrom, Jon
通讯作者：
Lindstrom, Jon
DOI：
10.1073/pnas.1602619113
发表时间：
2016-08-23
影响因子：
11.1
作者：
Kouvatsos, Nikolaos;Giastas, Petros;Tzartos, Socrates J.
通讯作者：
Tzartos, Socrates J.
影响因子：
7.3
作者：
Carbone, A-L;Moroni, M.;Bermudez, I.
通讯作者：
Bermudez, I.