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G protein-coupled receptors (GPCRs) orchestrate many physiological functions and are a crucial target in drug discovery. Adhesion GPCRs (aGPCRs), the second largest family within this superfamily, are promising yet underexplored targets for treating various diseases, including obesity, psychiatric disorders, and cancer. However, the receptors' unique and complex structure and miscellaneous interactions complicate comprehensive pharmacological studies. Despite recent progress in determining structures and elucidation of the activation mechanism, the function of many receptors remains to be determined. This review consolidates current knowledge on aGPCR ligands, focusing on small molecule orthosteric ligands and allosteric modulators identified for the ADGRGs subfamily (subfamily VIII), (GPR56/ADGRG1, GPR64/ADGRG2, GPR97/ADGRG3, GPR114/ADGRG5, GPR126/ADGRG6, and GPR128/ADGRG7). We discuss challenges in hit identification, target validation, and drug discovery, highlighting molecular compositions and recent structural breakthroughs. ADGRG ligands can offer new insights into aGPCR modulation and have significant potential for novel therapeutic interventions targeting various diseases. Adhesion GPCRs (aGPCRs) are emerging as a promising yet underexplored drug target for diseases like cancer, obesity, and psychiatric disorders. In this review, Liessmann et al. discuss the ADGRG subfamily, highlighting known small molecule and peptide ligands, structural breakthroughs, and challenges in drug discovery for this family. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that renal fibrosis plays a key role in the development of hypertensive nephropathy (HTN). Therefore, a better understanding of the underlying mechanism of renal fibrosis regulation in HTN would be critical for designing rational strategies for therapeutic interventions. In this study, we revealed that GPR97, a novel identified adhesion G coupled receptor, plays an important role in the regulation of Wnt/β‐catenin signaling, which is the crucial driver of renal fibrosis in HTN. First, we identified that the expression of GPR97 correlated with the β‐catenin expression in renal biopsy from patients with HTN. Moreover, we found that GPR97 deficiency inhibited Wnt/β‐catenin signaling in mice with HTN, as evidenced by the reduction of β‐catenin expression and downstream target proteins, including MMP7 and Fibronectin. Mechanistically, we found that GPR97 could directly bind with Wnt1 in cultured tubular cells and TGF‐β1 treatment enhanced the binding ability of GPR97 and Wnt1. In addition, the gene silencing of GPR97 could decrease the Wnt1‐induced fibrotic phenotype of tubular cells and inflammatory responses, suggesting that the binding of GPR97 and Wnt1 promoted Wnt/β‐catenin signaling. Collectively, our studies reveal that GPR97 is a regulator of Wnt/β‐catenin signaling in HTN, and targeting GPR97 may be a novel therapeutic strategy for HTN treatment. [ABSTRACT FROM AUTHOR]

Skin psoriasis is defined as receiving external stimulation to activate skin dendritic cells (DCs) which can release interleukin 23 (IL-23) to interlink the innate and adaptive immunity as well as induce T helper 17 (Th17) cell differentiation leading to elevated production of interleukin 17 (IL-17) for keratinocytes over production. This autoimmune loop in psoriasis pathogenesis is influenced by G protein-coupled receptor (GPCR) signalling transduction, and in particular, function of adhesion molecule GPR97 in psoriasis endures to be utterly addressed. In this research, our team allocated GPR97 depletion (GPR97-/-), GPR97 conditional depletion on dendritic cell (DC-cKO), and keratin 14-conditional knockout (K14-cKO) mice models to explore the function of GPR97 which influences keratinocytes and skin immunity. It was found that significantly aggravated psoriasis-like lesion in GPR97-/- mice. In addition, hyperproliferative keratinocytes as well as accumulation of DCs and Th17 cells were detected in imiquimod (IMQ)-induced GPR97-/- mice, which was consistent with the results in DC-cKO and K14-cKO psoriasis model. Additional investigations indicated that beclomethasone dipropionate (BDP), an agonist of GPR97, attenuated the psoriasis-like skin disease and restricted HaCaT cells abnormal proliferation as well as Th17 cells differentiation. Particularly, we found that level of NF-κB p65 was increased in GPR97-/- DCs and BDP could inhibit p65 activation in DCs. Role of GPR97 is indispensable and this adhesion receptor may affect immune cell enrichment and function in skin and alter keratinocytes proliferation as well as differentiation in psoriasis. [Display omitted] • GPR97 regulates DC activation and following Th17 cell differentiation. • Beclomethasone dipropionate significantly restrict psoriasis pathogenesis via GPR97. • GPR97 deletion activate NF-kB signalling pathway leading to psoriatic aggravation. [ABSTRACT FROM AUTHOR]