Drd2-KO Mouse

Drd2, the dopamine D2 receptor gene, plays a pivotal role in the dopamine signaling pathway. Dopamine is crucial in integrating metabolic signals with cognitive, perceptual, and appetitive functions related to feeding, and Drd2 is a key component in this neurotransmission process [3]. It has also been linked to various physiological and pathological processes, making it an important target for understanding related biological functions [6].

In breast cancer, Drd2 acts as a tumor suppressor. Its down-regulation due to promoter methylation was observed, and higher expression correlated with longer survival, especially in HER2-positive patients. Ectopic expression inhibited tumorigenesis, induced apoptosis and necroptosis, restricted NF-κB signaling, and facilitated M1 macrophage polarization and pyroptosis [1].

In glioblastoma, chronic stress promoted tumor progression by up-regulating dopamine and Drd2. Down-regulation or inhibition of Drd2 abolished this promoting effect, indicating its role in the DRD2/ERK/β-catenin axis and the Dopamine/ERK/TH positive feedback loop [2].

In prostate cancer, the extracellular matrix in synthetic hydrogel-based organoids regulated the response to Drd2 inhibitors, and in vivo, a Drd2 inhibitor showed a strong anti-tumor response [4].

In age-related macular degeneration, DRD2 activation inhibited choroidal neovascularization [5].

In glioblastoma, the DRD2 antagonist haloperidol increased temozolomide sensitivity by promoting autophagy-induced ferroptosis through endoplasmic reticulum stress [7].

In summary, Drd2 is involved in multiple disease processes, with its function as a potential tumor suppressor in breast cancer, a promoter of glioblastoma progression under chronic stress, and a regulator of therapeutic response in prostate cancer. Its role in inhibiting choroidal neovascularization in age-related macular degeneration and enhancing temozolomide sensitivity in glioblastoma also highlights its importance in disease-related biological functions. These findings from in vivo and functional studies contribute to understanding the mechanisms of these diseases and potentially developing new therapeutic strategies.

References:

1. Tan, Yiqing, Sun, Ran, Liu, Lei, Ren, Guosheng, Xiang, Tingxiu. 2021. Tumor suppressor DRD2 facilitates M1 macrophages and restricts NF-κB signaling to trigger pyroptosis in breast cancer. In Theranostics, 11, 5214-5231. doi:10.7150/thno.58322. https://pubmed.ncbi.nlm.nih.gov/33859743/

2. Wang, Yan, Wang, Xiang, Wang, Kai, Yu, Rutong, Zhou, Xiuping. 2023. Chronic stress accelerates glioblastoma progression via DRD2/ERK/β-catenin axis and Dopamine/ERK/TH positive feedback loop. In Journal of experimental & clinical cancer research : CR, 42, 161. doi:10.1186/s13046-023-02728-8. https://pubmed.ncbi.nlm.nih.gov/37415171/

3. Sun, Xue, Luquet, Serge, Small, Dana M. 2017. DRD2: Bridging the Genome and Ingestive Behavior. In Trends in cognitive sciences, 21, 372-384. doi:10.1016/j.tics.2017.03.004. https://pubmed.ncbi.nlm.nih.gov/28372879/

4. Mosquera, Matthew J, Kim, Sungwoong, Bareja, Rohan, Elemento, Olivier, Singh, Ankur. 2021. Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors. In Advanced materials (Deerfield Beach, Fla.), 34, e2100096. doi:10.1002/adma.202100096. https://pubmed.ncbi.nlm.nih.gov/34676924/

5. Mathis, Thibaud, Baudin, Florian, Mariet, Anne-Sophie, Hunot, Stéphane, Sennlaub, Florian. 2024. DRD2 activation inhibits choroidal neovascularization in patients with Parkinson's disease and age-related macular degeneration. In The Journal of clinical investigation, 134, . doi:10.1172/JCI174199. https://pubmed.ncbi.nlm.nih.gov/39012703/

6. Zhang, Yao, Yu, Jian-Gang, Wen, Wen. 2024. Recent Advances in representative small-molecule DRD2 inhibitors: Synthetic Routes and clinical applications. In European journal of medicinal chemistry, 277, 116731. doi:10.1016/j.ejmech.2024.116731. https://pubmed.ncbi.nlm.nih.gov/39098130/

7. Shi, Linyong, Chen, Hanning, Chen, Kunxiang, Li, Hong, Lu, Yuntao. . The DRD2 Antagonist Haloperidol Mediates Autophagy-Induced Ferroptosis to Increase Temozolomide Sensitivity by Promoting Endoplasmic Reticulum Stress in Glioblastoma. In Clinical cancer research : an official journal of the American Association for Cancer Research, 29, 3172-3188. doi:10.1158/1078-0432.CCR-22-3971. https://pubmed.ncbi.nlm.nih.gov/37249604/