GPRC6A mediates the non-genomic effects of steroids.
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.
Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38103, USA. mpi@uthsc.edu
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D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013739:Testosterone / Q000276:immunology / Q000494:pharmacology*
C515750:GPRC6A protein, mouse; D043562:Receptors, G-Protein-Coupled; D013739:Testosterone; D048049:Extracellular Signal-Regulated MAP Kinases