Gabrd-KO Mouse

Gabrd, encoding the δ subunit of extrasynaptic GABAA receptors, is involved in inhibitory neurotransmission within the central nervous system [3]. The GABAA receptor system plays a crucial role in regulating neuronal excitability, and Gabrd-containing receptors are part of important pathways related to normal brain function, such as those involved in maintaining the balance of neural activity [2].

Gain-of-function variants in Gabrd were identified in patients with neurodevelopmental disorders and generalized epilepsy. Electrophysiological measurements showed that some variants led to altered function of α1β3δ and α4β2δ GABAA receptors, with four of five functional variants resulting in gain-of-function effects. Patients with gain-of-function variants had common phenotypes including neurodevelopmental disorders with behavioral issues, intellectual disability, and generalized epilepsy [3].

In cancer research, Gabrd is upregulated in colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC), and gastric cancer (GC). In CRC, its overexpression is associated with later pTNM stages and poor patient survival, and it accelerates cell growth and migration. In ESCC, it collaborates with DEPDC1B to regulate cancer progression, and in GC, it accelerates tumour progression via regulating the CCND1 signalling pathway [1,4,5]. Conversely, in breast cancer, Gabrd may inhibit cancer progression by regulating the cell cycle [6].

In summary, Gabrd is essential for proper inhibitory neurotransmission in the central nervous system. Research on Gabrd, especially through the study of its gain-of-function and loss-of-function effects in human subjects and in cancer cell models, has revealed its significance in neurodevelopmental disorders, epilepsy, and multiple types of cancer. These findings may provide new directions for understanding the mechanisms of these diseases and developing potential treatment strategies.

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. Luscher, Bernhard, Maguire, Jamie L, Rudolph, Uwe, Sibille, Etienne. 2023. GABAA receptors as targets for treating affective and cognitive symptoms of depression. In Trends in pharmacological sciences, 44, 586-600. doi:10.1016/j.tips.2023.06.009. https://pubmed.ncbi.nlm.nih.gov/37543478/

3. Ahring, Philip K, Liao, Vivian W Y, Gardella, Elena, Chebib, Mary, Møller, Rikke S. . Gain-of-function variants in GABRD reveal a novel pathway for neurodevelopmental disorders and epilepsy. In Brain : a journal of neurology, 145, 1299-1309. doi:10.1093/brain/awab391. https://pubmed.ncbi.nlm.nih.gov/34633442/

4. 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/

5. 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/

6. Wu, Liang, Zhang, Yue, Zheng, Chunlei, Zhao, Fuqiang, Lin, Yan. . Gamma-Aminobutyric Acid Type A Receptor Subunit Delta (GABRD) Inhibits Breast Cancer Progression by Regulating the Cell Cycle. In Iranian journal of public health, 52, 542-552. doi:10.18502/ijph.v52i3.12137. https://pubmed.ncbi.nlm.nih.gov/37124892/