TACR1,也称为神经激肽1受体(NK1R),是一种G蛋白偶联受体,主要在神经元和内分泌细胞中表达。它是一种重要的信号分子,参与调节疼痛、情绪和行为等多种生理和病理过程。TACR1的主要配体是神经肽P物质(SP),SP与TACR1结合后可以激活多种下游信号通路,包括磷脂酶C、蛋白激酶C和钙调蛋白依赖性蛋白激酶等。TACR1的激活可以导致神经元兴奋、血管扩张、平滑肌收缩和炎症反应等效应。
根据以上检索的参考文献内容,我们可以看到TACR1在多种疾病和生理过程中发挥重要作用。例如,TACR1的激活可以促进乳腺癌的生长、侵袭和转移,这是由于SP与TACR1结合后,可以促进TACR1high癌细胞的死亡,并释放单链RNA(ssRNA),ssRNA作用于邻近肿瘤的Toll样受体7(TLR7),激活促转移基因表达程序[1]。此外,TACR1基因多态性与术后恶心和呕吐的发生率和严重程度相关,其中rs3755468-SNP与女性患者的术后恶心和呕吐发生率降低相关[2]。在乳腺癌患者中,TACR1基因多态性可以作为预测对神经激肽-1受体拮抗剂为基础的抗恶心治疗反应的药物基因组学预测因子[3]。TACR1基因变异与酒精偏好大鼠的酒精自我给药减少和酒精奖励降低相关,并且与人类酒精依赖相关[4]。TACR1基因敲除小鼠表现出过度活跃的行为,这与注意力缺陷多动障碍(ADHD)的人类表型相似,并且TACR1基因的DNA序列变化与ADHD的易感性增加相关[5]。TACR1基因多态性与双相情感障碍(BPAD)、酒精依赖综合征(ADS)和ADHD相关,并且这些情感障碍之间存在共享的分子病理生理学[6]。TACR1基因变异与膝关节骨关节炎的疼痛相关,其中rs11688000变异与症状性骨关节炎的风险降低相关[7]。TACR1基因型可以预测对酒精线索的fMRI反应和酒精依赖程度,其中rs3771863、rs3755459和rs1106855与酒精线索的反应相关[8]。最后,TACR1的靶向抑制可以显著降低神经母细胞瘤的生长,并诱导细胞凋亡,为神经母细胞瘤的治疗提供了新的思路[9]。此外,TACR1基因变异与二异氰酸酯诱导的哮喘相关,其中rs2287231变异与哮喘风险相关[10]。
综上所述,TACR1基因在多种疾病和生理过程中发挥重要作用,包括乳腺癌、术后恶心和呕吐、酒精依赖、ADHD、双相情感障碍、骨关节炎、酒精依赖和神经母细胞瘤等。TACR1基因的变异和表达异常与这些疾病的发病机制和临床表型密切相关。因此,TACR1基因可以作为这些疾病的潜在治疗靶点和药物基因组学预测因子。未来,我们可以通过进一步研究TACR1基因的功能和机制,为这些疾病的治疗和预防提供新的思路和策略。
参考文献:
1. Padmanaban, Veena, Keller, Isabel, Seltzer, Ethan S, Kerner, Zachary, Tavazoie, Sohail F. 2024. Neuronal substance P drives metastasis through an extracellular RNA-TLR7 axis. In Nature, 633, 207-215. doi:10.1038/s41586-024-07767-5. https://pubmed.ncbi.nlm.nih.gov/39112700/
2. Hayase, T, Sugino, S, Moriya, H, Yamakage, M. 2015. TACR1 gene polymorphism and sex differences in postoperative nausea and vomiting. In Anaesthesia, 70, 1148-59. doi:10.1111/anae.13082. https://pubmed.ncbi.nlm.nih.gov/26012530/
3. Ghorbani, Marziyeh, Namazi, Soha, Dehghani, Mehdi, Khalvati, Bahman, Dehshahri, Ali. 2024. Gene polymorphisms of TACR1 serve as the potential pharmacogenetic predictors of response to the neurokinin-1 receptor antagonist-based antiemetic regimens: a candidate-gene association study in breast cancer patients. In Cancer chemotherapy and pharmacology, 94, 237-250. doi:10.1007/s00280-024-04661-9. https://pubmed.ncbi.nlm.nih.gov/38678150/
4. Schank, Jesse R, Tapocik, Jenica D, Barbier, Estelle, Rice, Kenner C, Heilig, Markus. 2013. Tacr1 gene variation and neurokinin 1 receptor expression is associated with antagonist efficacy in genetically selected alcohol-preferring rats. In Biological psychiatry, 73, 774-81. doi:10.1016/j.biopsych.2012.12.027. https://pubmed.ncbi.nlm.nih.gov/23419547/
5. Yan, T C, McQuillin, A, Thapar, A, Stanford, S C, Gurling, H. 2009. NK1 (TACR1) receptor gene 'knockout' mouse phenotype predicts genetic association with ADHD. In Journal of psychopharmacology (Oxford, England), 24, 27-38. doi:10.1177/0269881108100255. https://pubmed.ncbi.nlm.nih.gov/19204064/
6. Sharp, Sally I, McQuillin, Andrew, Marks, Michael, Curtis, David, Gurling, Hugh M D. 2014. Genetic association of the tachykinin receptor 1 TACR1 gene in bipolar disorder, attention deficit hyperactivity disorder, and the alcohol dependence syndrome. In American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, 165B, 373-80. doi:10.1002/ajmg.b.32241. https://pubmed.ncbi.nlm.nih.gov/24817687/
7. Warner, S C, Walsh, D A, Laslett, L L, Doherty, M, Valdes, A M. 2017. Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene. In European journal of pain (London, England), 21, 1277-1284. doi:10.1002/ejp.1027. https://pubmed.ncbi.nlm.nih.gov/28493529/
8. Blaine, Sara, Claus, Eric, Harlaar, Nicole, Hutchison, Kent. 2012. TACR1 genotypes predict fMRI response to alcohol cues and level of alcohol dependence. In Alcoholism, clinical and experimental research, 37 Suppl 1, E125-30. doi:10.1111/j.1530-0277.2012.01923.x. https://pubmed.ncbi.nlm.nih.gov/23078527/
9. Henssen, Anton G, Odersky, Andrea, Szymansky, Annabell, Bergmann, Andreas, Schulte, Johannes H. . Targeting tachykinin receptors in neuroblastoma. In Oncotarget, 8, 430-443. doi:10.18632/oncotarget.13440. https://pubmed.ncbi.nlm.nih.gov/27888795/
10. Bernstein, David I, Lummus, Zana L, Kesavalu, Banu, Weirauch, Matthew T, Kaufman, Kenneth. 2018. Genetic variants with gene regulatory effects are associated with diisocyanate-induced asthma. In The Journal of allergy and clinical immunology, 142, 959-969. doi:10.1016/j.jaci.2018.06.022. https://pubmed.ncbi.nlm.nih.gov/29969634/