Non-classical testosterone signaling in spermatogenic GC-2 cells is mediated through ZIP9 interacting with Gnα11

Shihan, Mazen; Chan, Kai-Hui; Konrad, Lutz; Scheiner‐Bobis, Georgios

doi:10.1016/j.cellsig.2015.07.013

Cited by 40 publications

(18 citation statements)

References 44 publications

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“…Previous studies showed that epigenetic factors and availability of cofactors influence the AR-regulated transcriptome and finally determine the final response of the cell [43,44]. Moreover, several papers reported that testosterone binding to ZIP9 activates different G proteins and various downstream signaling events in cell type-specific manner [8,12,45,46].…”

Section: Discussionmentioning

confidence: 99%

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

Kamińska

Marek

Pardyak

et al. 2020

IJMS

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Our recent study demonstrated altered expression of Notch ligands, receptors, and effector genes in testes of pubertal rats following reduced androgen production or signaling. Herein we aimed to explore the role of nuclear androgen receptor (AR) and membrane androgen receptor (Zrt- and Irt-like protein 9; ZIP9) in the regulation of Notch pathway activation in rodent Sertoli cells. Experiments were performed using TM4 and 15P-1 Sertoli cell lines and rat primary Sertoli cells (PSC). We found that testosterone (10−8 M–10−6 M) increased the expression of Notch1 receptor, its active form Notch1 intracellular domain (N1ICD) (p < 0.05, p < 0.01, p < 0.001), and the effector genes Hey1 (p < 0.05, p < 0.01, p < 0.001) and Hes1 (p < 0.05, p < 0.001) in Sertoli cells. Knockdown of AR or ZIP9 as well as antiandrogen exposure experiments revealed that (i) action of androgens via both AR and ZIP9 controls Notch1/N1ICD expression and transcriptional activity of recombination signal binding protein (RBP-J), (ii) AR-dependent signaling regulates Hey1 expression, (iii) ZIP9-dependent pathway regulates Hes1 expression. Our findings indicate a crosstalk between androgen and Notch signaling in Sertoli cells and point to cooperation of classical and non-classical androgen signaling pathways in controlling Sertoli cell function.

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Section: Discussionmentioning

confidence: 99%

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

Kamińska

Marek

Pardyak

et al. 2020

IJMS

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“…GnRH‐A treatment abrogates steroidogenesis, thus abolishing testosterone production. The effects of such testosterone deprivation were assessed by measuring the abundance of two known androgen binding proteins, the classical androgen receptor (AR) and ZIP9, a Zn 2+ transporter from the family of the zinc‐regulated, iron‐regulated transporter (ZRT, IRT)‐like proteins that functions as a membrane‐bound testosterone receptor (Berg et al, ; Thomas et al, ; Shihan et al, ; Bulldan et al, ). AR expression was depressed, but not completely abolished, by the implant, based on the AR‐specific bands detectable immediately after implant removal (Week 0) that were slightly, but significantly, reduced compared to untreated controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, the GnRH‐A implant had a marked effect on the expression of ZIP9. The physiological impact of this receptor has not yet been fully explored, although ZIP9 is reported to function as a Zn 2+ transporter as well as a transmembrane receptor that interacts with testosterone, inducing the non‐classical signaling cascades triggered by this hormone (Berg et al, ; Thomas et al, ; Shihan et al, ; Bulldan et al, ). Ours is the first report to show that its expression is affected under minimal steroidogenesis, which strengthens the idea that ZIP9 participates in testosterone signaling.…”

Section: Discussionmentioning

confidence: 99%

Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines

Bulldan¹,

Shihan²,

Goericke-Pesch

et al. 2016

Molecular Reproduction Devel

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A gonadotropin-releasing hormone agonist (GnRH-A) implant induces hormonal castration in dogs that is associated with reduced prostate and testes size. We address the molecular events associated with hormonal castration by examining GnRH-A effects on expression and phosphorylation of a number of key signaling proteins. Male beagles were treated for 5 months with a GnRH-A implant, and then surgically castrated at 0, 3, 6, 12, and, 24 weeks after implant removal; untreated animals served as controls. GnRH-A treatment led to activation of c-Raf, Erk1/2, and, p53 in the testes. Phosphorylation of p53 occurred at Ser15, consistent with activation of the c-Raf-Erk1/2-p53 signaling cascade that triggers growth arrest or apoptosis. GnRH-A also suppressed the anti-apoptotic protein Bcl-xL; reduced phosphorylation of the transcription factors CREB and ATF1; and down-regulated expression of StAR and P450scc, proteins involved in steroidogenesis. Although androgen receptor expression was little affected by GnRH-A treatment, levels of ZIP9, a membrane-bound Zn transporter that mediates non-classical signaling of testosterone, were abrogated. All of these effects were reversed within 24 weeks after implant removal. Thus, molecular signatures of implant-dependent hormonal castration include reversible cell cycle arrest and apoptosis, loss of steroidogenesis, and reduced transcriptional activity. Mol. Reprod. Dev. 83: 1092-1101, 2016. © 2016 Wiley Periodicals, Inc.

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“…Studies of zinc transporters revealed that the deletion of zipt-7.1 causes sterility [ 58 ]. ZIP9 serves as a Zn 2+ transporter associated with the G-protein Gnα11, which mediates testosterone signaling in murine spermatogenic cells [ 59 ]. During ejaculation, Zn 2+ is transported into the nucleus [ 16 ], which is important for chromatin stabilization [ 60 , 61 ].…”

Section: Zinc and Fertilitymentioning

confidence: 99%

The Role of Zinc in Male Fertility

Allouche-Fitoussi

Breitbart

2020

IJMS

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Several studies proposed the importance of zinc ion in male fertility. Here, we describe the properties, roles and cellular mechanisms of action of Zn2+ in spermatozoa, focusing on its involvement in sperm motility, capacitation and acrosomal exocytosis, three functions that are crucial for successful fertilization. The impact of zinc supplementation on assisted fertilization techniques is also described. The impact of zinc on sperm motility has been investigated in many vertebrate and invertebrate species. It has been reported that Zn2+ in human seminal plasma decreases sperm motility and that Zn2+ removal enhances motility. Reduction in the intracellular concentration of Zn2+ during epididymal transit allows the development of progressive motility and the subsequent hyper activated motility during sperm capacitation. Extracellular Zn2+ affects intracellular signaling pathways through its interaction with the Zn2+ sensing receptor (ZnR), also named GPR39. This receptor was found in the sperm tail and the acrosome, suggesting the possible involvement of Zn2+ in sperm motility and acrosomal exocytosis. Our studies showed that Zn2+ stimulates bovine sperm acrosomal exocytosis, as well as human sperm hyper-activated motility, were both mediated by GPR39. Zn2+ binds and activates GPR39, which activates the trans-membrane-adenylyl-cyclase (tmAC) to catalyze cAMP production. The NHE (Na+/H+-exchanger) is activated by cAMP, leading in increased pHi and activation of the sperm-specific Ca2+ channel CatSper, resulting in an increase in [Ca2+]i, which, together with HCO3−, activates the soluble adenylyl-cyclase (sAC). The increase in [cAMP]i activates protein kinase A (PKA), followed by activation of the Src-epidermal growth factor receptor-Pphospholipase C (Src-EGFR-PLC) cascade, resulting in inositol-triphosphate (IP3) production, which mobilizes Ca2+ from the acrosome, causing a further increase in [Ca2+]i and the development of hyper-activated motility. PKA also activates phospholipase D1 (PLD1), leading to F-actin formation during capacitation. Prior to the acrosomal exocytosis, PLC induces phosphadidylinositol-4,5-bisphosphate (PIP2) hydrolysis, leading to the release of the actin-severing protein gelsolin to the cytosol, which is activated by Ca2+, resulting in F-actin breakdown and the occurrence of acrosomal exocytosis.

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Non-classical testosterone signaling in spermatogenic GC-2 cells is mediated through ZIP9 interacting with Gnα11

Cited by 40 publications

References 44 publications

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

Crosstalk between Androgen-ZIP9 Signaling and Notch Pathway in Rodent Sertoli Cells

Signaling events associated with gonadotropin releasing hormone‐agonist‐induced hormonal castration and its reversal in canines

The Role of Zinc in Male Fertility

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