Journal of Biological Chemistry
Volume 285, Issue 51, 17 December 2010, Pages 39953-39964
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Signal Transduction
GPRC6A Mediates the Non-genomic Effects of Steroids*

https://doi.org/10.1074/jbc.M110.158063Get rights and content
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The identity of the putative G-protein coupled receptor (GPCR) that mediates the non-genomic effects of androgens is unknown. We present in vitro and in vivo evidence that the orphan GPRC6A receptor, a widely expressed calcium and amino acid sensing GPCR, transduces the non-genomic effects of testosterone and other steroids. Overexpression of GPRC6A imparts the ability of extracellular testosterone to illicit a rapid, non-genomic signaling response in HEK-293 cells lacking the androgen receptor. Conversely, testosterone-stimulated rapid signaling and phosphorylation of ERK is attenuated in bone marrow stromal cells derived from GPRC6A−/− mice and in 22Rv1 prostate cancer cells after siRNA-mediated knockdown of GPRC6A. Compared with wild-type controls, GPRC6A−/− null mice exhibit significantly less ERK activation and Egr-1 expression in both bone marrow and testis in response to pharmacological doses of testosterone in vivo. In addition, testosterone administration results in suppression of luteinizing hormone in wild-type male mice, but paradoxically stimulates serum luteinizing hormone levels in GPRC6A−/− null mice. These results suggest that GPRC6A is functionally important in regulating non-genomic effects of androgens in multiple tissues.

G-protein Coupled Receptors (GPCR)
Metabolic Regulation
Receptors
Signal Transduction
Steroid Hormone Receptor
Androgen
GPRC6A
Nongenomic Effect

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*

This work was supported, in whole or in part, by National Institutes of Health Grant R01-AR37308 (to L. D. Q.) and Center of Biomedical Research Excellence, Epithelial Function in Health and Disease Grant P20 RR017686 (to M. P.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.