Extracellular Ca2+ aggravates IgE-induced allergic reaction in mast cells through GPRC6A, a novel family C G-protein-coupled receptor

Liu, Guirong; Han, Shiwen; Jiang, Songsong; Jiang, Yuchi; Chen, Cheng; Sun, Na; Che, Huilian

doi:10.1016/j.lfs.2022.121013

Cited by 2 publications

(1 citation statement)

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“…Androgens can also activate signal transduction pathways independently of transcription, via a mechanism called non-genomic signaling (Gorczynska and Handelsman, 1995). These rapid androgen actions can be mediated by second messenger signaling pathways such as activation of intracellular kinases (eg MAPK, PI-3K) or increases in intracellular Ca 2+ (Estrada et al, 2003; Gatson and Singh, 2007; Gatson et al, 2006; Guo et al, 2002; Kang et al, 2004; Lieberherr and Grosse, 1994; Liu et al, 2022). Androgen signaling occurs in the absence of nuclear AR (Guo et al, 2002; Hatzoglou et al, 2005; Pi et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Testosterone acts through membrane protein GPRC6A to cause cardiac edema in zebrafish embryos

Zadmajid

Gorelick

2023

Preprint

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Androgen actions are classically thought to be mediated by intracellular androgen receptors (AR), but they can also exert non-genomic effects via binding to integral membrane proteins. Although several putative membrane androgen receptors were cloned and characterized in vitro, their function as androgen receptors in vivo remains to be further investigated. Here, we used a chemical-genetic screen in zebrafish and found that the G-protein coupled receptor GPRC6A mediates non-genomic androgen action during embryonic development. Exposure to three androgens, 5α-Androstane-3,17-dione (androstanedione), dihydrotestosterone (DHT), and testosterone, caused cardiac edema or tail curvature in wild-type embryos. ar mutant embryos also exhibited cardiac edema or tail curvature following exposure to these androgens, suggesting the involvement of ar-independent pathways. To identify the causative receptor, we mutated putative membrane androgen receptors gprc6a, hcar1-4, or zip9 genes and exposed mutant embryos to the androgens. We found that hcar1-4 and zip9 mutant embryos were susceptible to the identified androgens and developed cardiac edema or tail curvature phenotype following exposure. In contrast, we observed a significant reduction in cardiac edema phenotype in the gprc6a mutants compared to the wild-type embryos following testosterone treatment. Additionally, we exposed wild-type embryos to testosterone together with GPRC6A antagonists and observed a significant suppression of the cardiac edema phenotype. These results suggest that testosterone causes cardiac edema in zebrafish embryos by acting via the integral membrane protein GPRC6A, independently of nuclear androgen receptors. Overall, our study provides insights into non-genomic androgen signaling during embryonic development and identifies GPRC6A as a key receptor mediating androgen action.

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