Drd1-KO Mouse

Drd1, encoding the dopamine D1 receptor, is a crucial component of the dopaminergic system. Dopamine receptors, including D1-and D2-like receptors, are important therapeutic targets for various neurological syndromes, as well as cardiovascular and kidney diseases [1]. DRD1 activation can lead to enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF in direct pathway striatal medium spiny neurons, while dopamine depletion reduces BDNF responsiveness [3].

In a variety of disease-related studies, DRD1 has been shown to play diverse roles. In glioblastoma (GBM), DRD1 contributes to invasion and progression by regulating c-Myc entry into the nucleus, affecting the transcription of the UHRF1 gene [2]. In non-small cell lung cancer (NSCLC), DRD1 is a negative regulator of disease progression, affecting proliferation by inhibiting EGFR and ERK1/2 activation and regulating PD-L1 expression [4]. In ventilator-induced lung injury (VILI), DRD1 downregulation contributes to mechanical stretch-induced lung endothelial barrier dysfunction, and its activation can attenuate this effect [5]. Loss-of-function variants in DRD1 are associated with infantile parkinsonism-dystonia, suggesting a crucial role for the D1 receptor in motor control [6]. Also, the rs4532 locus of the DRD1 gene is related to hypertension, especially in East Asians [7].

In conclusion, Drd1 is essential in regulating multiple biological processes and is implicated in various disease conditions, including neurological, cardiovascular, and cancer-related diseases. The study of Drd1 using gene knockout or other functional models has provided valuable insights into its role in these diseases, highlighting its potential as a therapeutic target.

References:

1. Xiao, Peng, Yan, Wei, Gou, Lu, Yu, Xiao, Shao, Zhenhua. 2021. Ligand recognition and allosteric regulation of DRD1-Gs signaling complexes. In Cell, 184, 943-956.e18. doi:10.1016/j.cell.2021.01.028. https://pubmed.ncbi.nlm.nih.gov/33571432/

2. Xue, Zhiyi, Zhang, Yan, Zhao, Ruiqi, Wang, Jian, Zhou, Wenjing. 2024. The dopamine receptor D1 inhibitor, SKF83566, suppresses GBM stemness and invasion through the DRD1-c-Myc-UHRF1 interactions. In Journal of experimental & clinical cancer research : CR, 43, 25. doi:10.1186/s13046-024-02947-7. https://pubmed.ncbi.nlm.nih.gov/38246990/

3. Andreska, Thomas, Lüningschrör, Patrick, Wolf, Daniel, Stigloher, Christian, Sendtner, Michael. 2023. DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons. In Cell reports, 42, 112575. doi:10.1016/j.celrep.2023.112575. https://pubmed.ncbi.nlm.nih.gov/37252844/

4. Grant, Christopher E, Flis, Amy L, Toulabi, Leila, Sheppard, Heather, Ryan, Bríd M. 2024. DRD1 suppresses cell proliferation and reduces EGFR activation and PD-L1 expression in NSCLC. In Molecular oncology, 18, 1631-1648. doi:10.1002/1878-0261.13608. https://pubmed.ncbi.nlm.nih.gov/38572507/

5. Wang, Yan, Liu, Yu-Jian, Xu, Dun-Feng, Zhu, Xiao-Yan, Jiang, Lai. 2021. DRD1 downregulation contributes to mechanical stretch-induced lung endothelial barrier dysfunction. In Theranostics, 11, 2505-2521. doi:10.7150/thno.46192. https://pubmed.ncbi.nlm.nih.gov/33456556/

6. Reid, Kimberley M, Steel, Dora, Nair, Sanjana, Topf, Maya, Kurian, Manju A. 2023. Loss-of-Function Variants in DRD1 in Infantile Parkinsonism-Dystonia. In Cells, 12, . doi:10.3390/cells12071046. https://pubmed.ncbi.nlm.nih.gov/37048120/

7. Zhang, He, Sun, Zhao-qing, Liu, Shuang-shuang, Yang, Li-na. 2015. Association between GRK4 and DRD1 gene polymorphisms and hypertension: a meta-analysis. In Clinical interventions in aging, 11, 17-27. doi:10.2147/CIA.S94510. https://pubmed.ncbi.nlm.nih.gov/26730182/