Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Auton Neurosci. 2021 Jul;233:102807. doi: 10.1016/j.autneu.2021.102807. Epub 2021 Apr 10.
With its five receptor subtypes (D), dopamine is implicated in a myriad of neurological illnesses. Dopamine D receptor-based agonist therapy evokes nausea and vomiting. The signaling mechanisms by which dopamine D receptors evoke vomiting remains unknown. Phosphatidylinositol 3-kinases (PI3K)- and protein kinase C (PKC)-related signaling cascades stimulate vomiting post-injection of various emetogens in emetically competent animals. This study investigated potential mechanisms involved in dopamine D receptor-mediated vomiting using least shrews. We found that vomiting evoked by the selective dopamine D receptor agonist quinpirole (2 mg/kg, i.p.) was significantly suppressed by: i) a dopamine D preferring antagonist, sulpiride (s.c.); ii) a selective PI3K inhibitor, LY294002 (i.p.); iii) a PKCαβII inhibitor, GF109203X (i.p.); and iv) a selective inhibitor of extracellular signal-regulated protein kinase1/2 (ERK1/2), U0126 (i.p.). Quinpirole-evoked c-fos immunofluorescence in the nucleus tractus solitarius (NTS) was suppressed by pretreatment with sulpiride (8 mg/kg, s.c.). Western blot analysis of shrew brainstem emetic loci protein lysates revealed a significant and time-dependent increase in phosphorylation of Akt (protein kinase B (PKB)) at Ser473 following a 30-min exposure to quinpirole (2 mg/kg, i.p.). Pretreatment with effective antiemetic doses of sulpiride, LY294002, GF109203X, or U0126 significantly reduced quinpirole-stimulated phosphorylation of emesis-associated proteins including p-85PI3K, mTOR (Ser2448/2481), PKCαβII (Thr638/641), ERK1/2 (Thr202/204), and Akt (Ser473). Our results substantiate the implication of PI3K/mTOR/Akt and PI3K/PKCαβII/ERK1/2/Akt signaling pathways in dopamine D receptor-mediated vomiting. Potential novel antiemetics targeting emetic proteins associated with these signaling cascades may offer enhanced potency and/or efficacy against emesis.
多巴胺通过其五个受体亚型（D）参与多种神经疾病。基于多巴胺 D 受体的激动剂疗法会引起恶心和呕吐。多巴胺 D 受体引起呕吐的信号机制尚不清楚。在具有呕吐能力的动物中，注射各种催吐剂后，磷脂酰肌醇 3-激酶 (PI3K) 和蛋白激酶 C (PKC) 相关信号级联刺激呕吐。本研究使用鼩鼱研究了多巴胺 D 受体介导的呕吐涉及的潜在机制。我们发现，选择性多巴胺 D 受体激动剂喹吡罗（2 mg/kg，ip）引起的呕吐明显被以下物质抑制：i）多巴胺 D 受体首选拮抗剂舒必利（sc）；ii）PI3K 选择性抑制剂 LY294002（ip）；iii）PKCαβII 抑制剂 GF109203X（ip）；和 iv）细胞外信号调节蛋白激酶 1/2（ERK1/2）的选择性抑制剂 U0126（ip）。舒必利（8 mg/kg，sc）预处理可抑制喹吡罗引起的孤束核（NTS）中 c-fos 免疫荧光。对鼩鼱脑干呕吐部位蛋白裂解物的 Western blot 分析显示，喹吡罗（2 mg/kg，ip）暴露 30 分钟后，Akt（蛋白激酶 B（PKB））在 Ser473 处的磷酸化显著且呈时间依赖性增加。舒必利、LY294002、GF109203X 或 U0126 的有效止吐剂量预处理可显著降低喹吡罗刺激的与呕吐相关的蛋白磷酸化，包括 p-85PI3K、mTOR（Ser2448/2481）、PKCαβII（Thr638/641）、ERK1/2（Thr202/204）和 Akt（Ser473）。我们的结果证实了 PI3K/mTOR/Akt 和 PI3K/PKCαβII/ERK1/2/Akt 信号通路在多巴胺 D 受体介导的呕吐中的作用。针对这些信号级联中与呕吐相关的蛋白的潜在新型止吐药可能会提高对呕吐的效力和/或疗效。
