title: Non-classical testosterone signaling in spermatogenic GC-2 cells is mediated through ZIP9 interacting with Gnα11.
abstract: Although classical and non-classical signaling of testosterone has been documented in several investigations, the nature of the receptor involved in the non-classical pathway remains a source of controversy. While some investigators favor the exclusive participation of the cytosolic/nuclear androgen receptor (AR) in both pathways, others propose a membrane-bound receptor as the mediator of the non-classical testosterone signaling. Evidence is provided here that in the spermatogenic cell line GC-2 the non-classical signaling pathway of testosterone, characterized through the activation of Erk1/2 and transcription factors like CREB or ATF-1, is not mediated through the classical nuclear androgen receptor (AR) but rather by a membrane-associated receptor. This receptor is ZIP9, a Zn(2+) transporter from the family of the ZRT, IRT-like proteins (ZRT=zinc-regulated transporter; IRT=iron-regulated transporter), which directly interacts with the G-protein Gnα11. siRNA-induced abrogation of the expression of either of these two proteins, whose close contacts are demonstrated by an in situ proximity assay, completely prevents all non-classical signaling effects of testosterone addressed. In contrast, silencing of AR expression does not influence the same signaling events. The identification of ZIP9/Gnα11 interactions as the mediators of the non-classical testosterone signaling cascade in spermatogenic GC-2 cells might help to supplement our knowledge concerning the role of testosterone in male fertility and reproduction.
authors.affiliation: Institut für Veterinär-Physiologie und -Biochemie, Fachbereich Veterinärmedizin, Justus-Liebig-Universität, Giessen, Germany.
authors.forename: Mazen
authors.initials: M
authors.lastname: Shihan
authors.affiliation: Zentrum f. Frauenheilkunde und Geburtshilfe, Fachbereich Medizin, Justus-Liebig-Universität, Giessen, Germany.
authors.forename: Kai-Hui
authors.initials: KH
authors.lastname: Chan
authors.affiliation: Zentrum f. Frauenheilkunde und Geburtshilfe, Fachbereich Medizin, Justus-Liebig-Universität, Giessen, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Konrad
authors.affiliation: Institut für Veterinär-Physiologie und -Biochemie, Fachbereich Veterinärmedizin, Justus-Liebig-Universität, Giessen, Germany; Zentrum f. Frauenheilkunde und Geburtshilfe, Fachbereich Medizin, Justus-Liebig-Universität, Giessen, Germany. Electronic address: Georgios.Scheiner-Bobis@vetmed.uni-giessen.de.
authors.forename: Georgios
authors.initials: G
authors.lastname: Scheiner-Bobis
mesh_terms: D051697:Activating Transcription Factor 1 / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D008297:Male; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D011944:Receptors, Androgen / Q000378:metabolism; D013091:Spermatogenesis; D013739:Testosterone / Q000502:physiology*
chemical_list: D051697:Activating Transcription Factor 1; C497100:Atf1 protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D044385:GTP-Binding Protein alpha Subunits; D011944:Receptors, Androgen; D013739:Testosterone; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Androgen receptor; GPCR; Gnα11; Testosterone; ZIP9