Gpr20, a class-A orphan G protein-coupled receptor (GPCR), constitutively activates Gi proteins even without ligand stimulation [3]. It is involved in regulating intracellular cAMP levels and mitogenic signaling, and may play a role in cellular processes such as controlling cell growth [3]. Gpr20 has been associated with lipid metabolism alteration in hepatic and intestinal cells, thus having a potential key role in metabolic diseases [4].

Gpr20 is selectively expressed in gastrointestinal stromal tumors (GIST) across all treatment lines, regardless of KIT/PDGFRA genotypes [1]. An antibody-drug conjugate (ADC) targeting Gpr20, DS-6157a, showed Gpr20 expression-dependent antitumor activity in GIST xenograft models, including those resistant to multiple tyrosine kinase inhibitors (TKIs) [1]. However, a phase I study of DS-6157a in advanced GIST patients showed lower-than-anticipated efficacy [5]. In early-onset preeclampsia (EO-PE), Siglec-6 upregulation promotes Gpr20 expression, leading to mitochondrial dysfunction in trophoblast cells, and Gpr20 downregulation can rescue the defects caused by Siglec-6 overexpression [2].

In conclusion, Gpr20 is a constitutively active GPCR with functions in regulating cAMP levels, cell growth, and lipid metabolism. Its selective expression in GIST makes it a potential therapeutic target, though challenges exist in translating this into effective therapies. In EO-PE, Gpr20 is involved in the Siglec-6-mediated mitochondrial dysfunction pathway, highlighting its role in pregnancy-related disorders. The study of Gpr20 through various models contributes to understanding its functions in different disease conditions.

References:

1. Iida, Kenji, Abdelhamid Ahmed, Amr H, Nagatsuma, Akiko Kawano, Demetri, George D, Agatsuma, Toshinori. 2021. Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with DS-6157a, a First-in-Class Antibody-Drug Conjugate. In Cancer discovery, 11, 1508-1523. doi:10.1158/2159-8290.CD-20-1434. https://pubmed.ncbi.nlm.nih.gov/33579785/

2. Jia, Yuanhui, Lu, Wenjing, Xie, Han, Liu, Wenqiang, Ying, Hao. 2024. Upregulation of Siglec-6 induces mitochondrial dysfunction by promoting GPR20 expression in early-onset preeclampsia. In Journal of translational medicine, 22, 674. doi:10.1186/s12967-024-05505-z. https://pubmed.ncbi.nlm.nih.gov/39039496/

3. Hase, Momoko, Yokomizo, Takehiko, Shimizu, Takao, Nakamura, Motonao. 2008. Characterization of an orphan G protein-coupled receptor, GPR20, that constitutively activates Gi proteins. In The Journal of biological chemistry, 283, 12747-55. doi:10.1074/jbc.M709487200. https://pubmed.ncbi.nlm.nih.gov/18347022/

4. López-Méndez, Iván, Méndez-Maldonado, Karla, Manzo-Francisco, Luis A, Uribe, Misael, Barbero-Becerra, Varenka J. 2020. G protein-coupled receptors: Key molecules in metabolic associated fatty liver disease development. In Nutrition research (New York, N.Y.), 87, 70-79. doi:10.1016/j.nutres.2020.12.019. https://pubmed.ncbi.nlm.nih.gov/33601216/

5. George, Suzanne, Heinrich, Michael C, Somaiah, Neeta, Shi, Julia, Naito, Yoichi. . A Phase I, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients with Advanced Gastrointestinal Stromal Tumor. In Clinical cancer research : an official journal of the American Association for Cancer Research, 29, 3659-3667. doi:10.1158/1078-0432.CCR-23-0640. https://pubmed.ncbi.nlm.nih.gov/37363962/