Adora2b, an adenosine receptor, is a key component of the adenosine signaling pathway. Among the four adenosine receptors (Adora1, Adora2a, Adora2b, Adora3), it has the lowest affinity for adenosine. Its activation is closely related to hypoxia-associated inflammation and immune-related processes. In the tumor microenvironment, especially in pancreatic ductal adenocarcinoma (PDAC), Adora2b activation can lead to immunosuppression, and it is also involved in fibrosis, perineural invasion, and changes in the vasculature [1,2].

In various in vivo studies using mouse models, targeting myocardial equilibrative nucleoside transporter ENT1 was shown to enhance myeloid Adora2b signaling, providing cardioprotection against ischemia and reperfusion injury [3]. In the context of midazolam-induced cognitive dysfunction, Adora2b -/- mice exhibited reduced hippocampal PER2 protein expression and T-maze alternation, suggesting a role for Adora2b in cognitive function [4]. Additionally, in the heart, APIP binds to and stabilizes Adora2b, playing a crucial role in cardioprotection against myocardial infarction, and the Adora2b D296G polymorphism from rs200741295 failed to bind to APIP and lost cardioprotective activity [5].

In summary, Adora2b is involved in multiple biological processes such as immune regulation, inflammation, and cardioprotection. Gene-knockout (KO) mouse models, like Adora2b -/- mice, have been instrumental in revealing its functions in disease conditions including PDAC, myocardial infarction, and midazolam-induced cognitive dysfunction, providing insights into potential therapeutic targets for these diseases.

References:

1. Strickland, Lincoln N, Faraoni, Erika Y, Ruan, Wei, Eltzschig, Holger K, Bailey-Lundberg, Jennifer M. 2023. The resurgence of the Adora2b receptor as an immunotherapeutic target in pancreatic cancer. In Frontiers in immunology, 14, 1163585. doi:10.3389/fimmu.2023.1163585. https://pubmed.ncbi.nlm.nih.gov/37187740/

2. Faraoni, Erika Y, Singh, Kanchan, Chandra, Vidhi, McAllister, Florencia, Bailey-Lundberg, Jennifer M. . CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer. In Cancer research, 83, 1111-1127. doi:10.1158/0008-5472.CAN-22-2553. https://pubmed.ncbi.nlm.nih.gov/36720042/

3. Ruan, Wei, Li, Jiwen, Choi, Seungwon, Mills, Tingting W, Eltzschig, Holger K. 2023. Targeting myocardial equilibrative nucleoside transporter ENT1 provides cardioprotection by enhancing myeloid Adora2b signaling. In JCI insight, 8, . doi:10.1172/jci.insight.166011. https://pubmed.ncbi.nlm.nih.gov/37288658/

4. Gile, Jennifer, Oyama, Yoshimasa, Shuff, Sydney, Eckle, Tobias. . A Role for the Adenosine ADORA2B Receptor in Midazolam Induced Cognitive Dysfunction. In Current pharmaceutical design, 26, 4330-4337. doi:10.2174/1381612826666200415171622. https://pubmed.ncbi.nlm.nih.gov/32294028/

5. Lim, Bitna, Jung, Kwangmin, Gwon, Youngdae, Bae, Jang-Whan, Jung, Yong-Keun. 2019. Cardioprotective role of APIP in myocardial infarction through ADORA2B. In Cell death & disease, 10, 511. doi:10.1038/s41419-019-1746-3. https://pubmed.ncbi.nlm.nih.gov/31263105/