Im Dong-Soon
Department of Biomedical and Pharmaceutical Sciences and Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul, 02446, Republic of Korea.
Laboratory of Pharmacology, College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
Arch Pharm Res. 2023 Jun;46(6):550-563. doi: 10.1007/s12272-023-01449-y. Epub 2023 May 25.
GPR35, an orphan receptor, has been waiting for its ligand since its cloning in 1998. Many endogenous and exogenous molecules have been suggested to act as agonists of GPR35 including kynurenic acid, zaprinast, lysophosphatidic acid, and CXCL17. However, complex and controversial responses to ligands among species have become a huge hurdle in the development of therapeutics in addition to the orphan state. Recently, a serotonin metabolite, 5-hydroxyindoleacetic acid (5-HIAA), is reported to be a high potency ligand for GPR35 by investigating the increased expression of GPR35 in neutrophils. In addition, a transgenic knock-in mouse line is developed, in which GPR35 was replaced with a human ortholog, making it possible not only to overcome the different selectivity of agonists among species but also to conduct therapeutic experiments on human GPR35 in mouse models. In the present article, I review the recent advances and prospective therapeutic directions in GPR35 research. Especially, I'd like to draw attention of readers to the finding of 5-HIAA as a ligand of GPR35 and lead to apply the 5-HIAA and human GPR35 knock-in mice to their research fields in a variety of pathophysiological conditions.
GPR35是一种孤儿受体，自1998年克隆以来一直在等待其配体。许多内源性和外源性分子被认为可作为GPR35的激动剂，包括犬尿烯酸、扎普司特、溶血磷脂酸和CXCL17。然而，除了其孤儿状态外，物种间对配体的复杂且有争议的反应已成为治疗药物开发中的巨大障碍。最近，通过研究嗜中性粒细胞中GPR35表达的增加，一种血清素代谢产物5-羟基吲哚乙酸（5-HIAA）被报道为GPR35的高效配体。此外，还培育了一种转基因敲入小鼠品系，其中GPR35被人类直系同源物取代，这不仅使得克服物种间激动剂的不同选择性成为可能，还能在小鼠模型中对人类GPR35进行治疗实验。在本文中，我回顾了GPR35研究的最新进展和潜在的治疗方向。特别是，我希望引起读者对5-HIAA作为GPR35配体这一发现的关注，并促使其在各种病理生理条件下将5-HIAA和人类GPR35敲入小鼠应用于他们的研究领域。
