The Contribution of Phospholipase C in Vomiting in the Least Shrew (Cryptotis Parva) Model of Emesis.
The Contribution of Phospholipase C in Vomiting in the Least Shrew (Cryptotis Parva) Model of Emesis.
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DOI：
10.3389/fphar.2021.736842
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发表时间：
2021
影响因子：
5.6
通讯作者：
Darmani NA
中科院分区：
文献类型：
--
作者：
Zhong W;Darmani NA
Gq 和 Gβγ 蛋白依赖性磷脂酶 C (PLC) 激活广泛参与 G 蛋白偶联受体 (GPCR) 介导的信号传导途径，这些信号传导途径与多种生理和病理事件有关。刺激多种 GPCR，例如 P 神经激肽 1-、多巴胺 D2/3-、组胺 H1- 和 mu-阿片受体，可导致呕吐。本研究的目的是通过在最小鼩鼱呕吐模型中评估 PLC 激活剂 (m-3M3FBS) 的催吐潜力和 PLC 抑制剂 (U73122) 的止吐功效，研究 PLC 在呕吐中的作用。我们发现，50 mg/kg（腹腔注射）剂量的 m-3M3FBS 会诱导约 90% 的测试最小鼩鼱呕吐，同时伴随着鼩鼱脑干背侧迷走复合体中 c-Fos 表达和 ERK1/2 磷酸化的显着增加，表明 m-3M3FBS 诱发呕吐中脑干催吐核的激活。通过使用多种止吐药进行预处理，包括以下拮抗剂/抑制剂，可减少 m-3M3FBS 诱发的呕吐：PLC (U73122)、L-型 Ca2+ 通道（硝苯地平）、IP3R (2-APB)、RyR 受体（丹曲林）、ERK1/2 (U0126)、PKC (GF109203X)、血清素能型3 受体（帕洛诺司琼）和神经激肽 1 受体（奈妥匹坦）。此外，PLC抑制剂U73122对多种催吐剂表现出广谱止吐作用，包括3型血清素（2-甲基-5-HT）-、神经激肽1受体（GR73632）、多巴胺D2/3（喹吡罗）-和毒蕈碱M1（McN-A-343）受体、L型Ca2+通道的选择性激动剂(FPL64176) 和肌/内质网 Ca2+-ATP 酶抑制剂 thapsigargin。总之，PLC 激活有助于呕吐，而 PLC 抑制则抑制多种催吐剂引起的呕吐。
Gq and Gβγ protein-dependent phospholipase C (PLC) activation is extensively involved in G protein-coupled receptor (GPCR)-mediated signaling pathways which are implicated in a wide range of physiological and pathological events. Stimulation of several GPCRs, such as substance P neurokinin 1-, dopamine D2/3-, histamine H1- and mu-opioid receptors, can lead to vomiting. The aim of this study was to investigate the role of PLC in vomiting through assessment of the emetic potential of a PLC activator (m-3M3FBS), and the antiemetic efficacy of a PLC inhibitor (U73122), in the least shrew model of vomiting. We find that a 50 mg/kg (i.p.) dose of m-3M3FBS induces vomiting in ∼90% of tested least shrews, which was accompanied by significant increases in c-Fos expression and ERK1/2 phosphorylation in the shrew brainstem dorsal vagal complex, indicating activation of brainstem emetic nuclei in m-3M3FBS-evoked emesis. The m-3M3FBS-evoked vomiting was reduced by pretreatment with diverse antiemetics including the antagonists/inhibitors of: PLC (U73122), L-type Ca2+ channel (nifedipine), IP3R (2-APB), RyR receptor (dantrolene), ERK1/2 (U0126), PKC (GF109203X), the serotoninergic type 3 receptor (palonosetron), and neurokinin 1 receptor (netupitant). In addition, the PLC inhibitor U73122 displayed broad-spectrum antiemetic effects against diverse emetogens, including the selective agonists of serotonin type 3 (2-Methyl-5-HT)-, neurokinin 1 receptor (GR73632), dopamine D2/3 (quinpirole)-, and muscarinic M1 (McN-A-343) receptors, the L-type Ca2+ channel (FPL64176), and the sarco/endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin. In sum, PLC activation contributes to emesis, whereas PLC inhibition suppresses vomiting evoked by diverse emetogens.
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