Gprc5c, an orphan G-protein coupled receptor belonging to the class C GPCR family, has diverse essential functions. It is involved in multiple biological processes, such as regulating hematopoietic stem cell (HSC) dormancy, and its associated pathways likely include those related to NF-κB, which impacts metabolism [1,4]. It also plays a role in the composition of cilia in the olfactory system, smooth muscle contraction, and osteoblast differentiation, and may function as a saccharide sensor [2,3,5,6]. Genetic models, like knockout mice, are valuable for studying its functions.

In acute myeloid leukemia (AML) patient cohorts, high Gprc5c levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression via NF-κB activation, altering metabolism with increased intracellular branched-chain amino acids (BCAAs). Loss of Gprc5c reversed this onco-metabolic profile and abrogated leukemia-initiating potential [1]. In olfactory neurons, Gprc5c deficiency altered sensory cilia structure and the localization of olfactory signalling proteins, increasing neuronal activity [2]. In smooth muscle cells, tamoxifen-inducible, SMC-specific Gprc5c knockout mice showed reduced angiotensin II-dependent calcium mobilization, contraction, and arterial hypertension, as Gprc5c facilitates AT1 receptor-ligand binding [3]. In osteoblasts, shRNA-mediated depletion of Gprc5c decreased bone marker expression and mineral deposition [6]. In pancreatic ductal adenocarcinoma, MLH1 inhibits metastasis by downregulating Gprc5c [7]. In the kidney, Gprc5c KO mice had altered acid-base homeostasis, and Gprc5c modulates Na+/H+ exchanger 3 (NHE3) activity at alkaline pH [8].

In conclusion, Gprc5c is crucial for multiple biological processes. Model-based research, especially using KO mouse models, has revealed its role in diseases such as AML, pancreatic cancer, and in regulating blood and urine pH. Understanding Gprc5c functions provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Zhang, Yu Wei, Velasco-Hernandez, Talia, Mess, Julian, Menendez, Pablo, Cabezas-Wallscheid, Nina. . GPRC5C drives branched-chain amino acid metabolism in leukemogenesis. In Blood advances, 7, 7525-7538. doi:10.1182/bloodadvances.2023010460. https://pubmed.ncbi.nlm.nih.gov/37639313/

2. Bhat, Sneha, Dietz, André, Senf, Katja, Westermann, Martin, Neuhaus, Eva Maria. 2023. GPRC5C regulates the composition of cilia in the olfactory system. In BMC biology, 21, 292. doi:10.1186/s12915-023-01790-0. https://pubmed.ncbi.nlm.nih.gov/38110903/

3. Wang, Tianpeng, Shao, Jingchen, Kumar, Shamit, Offermanns, Stefan, Wettschureck, Nina. 2024. Orphan GPCR GPRC5C Facilitates Angiotensin II-Induced Smooth Muscle Contraction. In Circulation research, 134, 1259-1275. doi:10.1161/CIRCRESAHA.123.323752. https://pubmed.ncbi.nlm.nih.gov/38597112/

4. Zhang, Yu Wei, Mess, Julian, Aizarani, Nadim, Grün, Dominic, Cabezas-Wallscheid, Nina. 2022. Hyaluronic acid-GPRC5C signalling promotes dormancy in haematopoietic stem cells. In Nature cell biology, 24, 1038-1048. doi:10.1038/s41556-022-00931-x. https://pubmed.ncbi.nlm.nih.gov/35725769/

5. Kawabata, Yuko, Takai, Shingo, Sanematsu, Keisuke, Jimi, Eijiro, Shigemura, Noriatsu. 2023. The G protein-coupled receptor GPRC5C is a saccharide sensor with a novel 'off' response. In FEBS letters, 597, 2006-2016. doi:10.1002/1873-3468.14695. https://pubmed.ncbi.nlm.nih.gov/37418589/

6. Dashti, Parisa, Thaler, Roman, Hawse, John R, van Wijnen, Andre J, Dudakovic, Amel. 2023. G-protein coupled receptor 5C (GPRC5C) is required for osteoblast differentiation and responds to EZH2 inhibition and multiple osteogenic signals. In Bone, 176, 116866. doi:10.1016/j.bone.2023.116866. https://pubmed.ncbi.nlm.nih.gov/37558192/

7. Liu, Wen-Jing, Lu, Jun, Zhou, Wei-Xun, Liu, Jian-Zhou, Zhou, Li. 2024. MLH1 Inhibits Metastatic Potential of Pancreatic Ductal Adenocarcinoma via Downregulation of GPRC5C. In Laboratory investigation; a journal of technical methods and pathology, 104, 102107. doi:10.1016/j.labinv.2024.102107. https://pubmed.ncbi.nlm.nih.gov/38964504/

8. Rajkumar, Premraj, Cha, Boyoung, Yin, Jianyi, Donowitz, Mark, Pluznick, Jennifer L. 2018. Identifying the localization and exploring a functional role for Gprc5c in the kidney. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 32, 2046-2059. doi:10.1096/fj.201700610RR. https://pubmed.ncbi.nlm.nih.gov/29196502/