GABRD, encoding the δ subunit of extrasynaptic GABAA receptors, is involved in GABAergic inhibitory neurotransmission. It plays a crucial role in regulating neurotransmission and is associated with pathways like epithelial-mesenchymal transition (EMT), angiogenesis, hedgehog signaling, and others in different biological contexts [1,3,4]. Genetic models such as gene knockout in relevant cell lines or animal models can be valuable for studying its functions.

In colorectal cancer, GABRD expression is increased compared to adjacent normal tissues. Overexpression accelerates cell growth and migration, while knockdown inhibits these processes, suggesting it promotes cancer progression and predicts poor prognosis [1]. In esophageal squamous cell carcinoma (ESCC), DEPDC1B knockdown leads to GABRD down-regulation, and GABRD silencing inhibits ESCC cell proliferation and migration. The two may collaborate to regulate ESCC progression through the PI3K/AKT/mTOR signaling pathway [2]. In gastric cancer, GABRD is up-regulated, and its knockdown induces apoptosis, cell cycle arrest, and suppresses tumor growth. It acts via regulating the CCND1 signaling pathway [3]. In rats, heroin self-administration causes GABRD gene hypomethylation in the nucleus accumbens, up-regulating its expression, and manipulating GABRD expression affects heroin-seeking behavior [5].

In conclusion, GABRD is significant in neurotransmission and plays diverse roles in multiple diseases, especially cancers. Findings from functional studies, including those resembling knockout-like effects in cell lines, show its involvement in promoting tumor progression in colorectal, esophageal, and gastric cancers. In the context of heroin-seeking behavior in rats, GABRD methylation and expression changes are key, suggesting potential as a therapeutic target in addiction.

References:

1. Niu, Gengming, Deng, Li, Zhang, Xiaotian, Meng, He, Ke, Chongwei. 2020. GABRD promotes progression and predicts poor prognosis in colorectal cancer. In Open medicine (Warsaw, Poland), 15, 1172-1183. doi:10.1515/med-2020-0128. https://pubmed.ncbi.nlm.nih.gov/33336074/

2. Yuan, Yunfeng, Ping, Wei, Zhang, Ruijie, Hao, Zhipeng, Zhang, Ni. 2022. DEPDC1B collaborates with GABRD to regulate ESCC progression. In Cancer cell international, 22, 214. doi:10.1186/s12935-022-02593-z. https://pubmed.ncbi.nlm.nih.gov/35706026/

3. Leng, Weibing, Ye, Jun, Wen, Zhenpeng, Song, Xilin, Liu, Kai. . GABRD Accelerates Tumour Progression via Regulating CCND1 Signalling Pathway in Gastric Cancer. In Journal of cellular and molecular medicine, 29, e70485. doi:10.1111/jcmm.70485. https://pubmed.ncbi.nlm.nih.gov/40145254/

4. Wu, Moxin, Kim, Keun Young, Park, Won Cheol, Kim, Eui Joong, Lee, Moon Young. 2020. Enhanced expression of GABRD predicts poor prognosis in patients with colon adenocarcinoma. In Translational oncology, 13, 100861. doi:10.1016/j.tranon.2020.100861. https://pubmed.ncbi.nlm.nih.gov/32891902/

5. Hong, Qingxiao, Xu, Wenjin, Lin, Zi, Zhou, Wenhua, Liu, Huifen. 2021. Role of GABRD Gene Methylation in the Nucleus Accumbens in Heroin-Seeking Behavior in Rats. In Frontiers in pharmacology, 11, 612200. doi:10.3389/fphar.2020.612200. https://pubmed.ncbi.nlm.nih.gov/33551813/