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Identification and characterization of membrane androgen receptors in the ZIP9 zinc transporter subfamily: I. Discovery in female Atlantic croaker and evidence ZIP9 mediates testosterone-induced apoptosis of ovarian follicle cells
Örebro University, School of Science and Technology. Marine Science Institute, University of Texas at Austin, United States . (Life Science)ORCID iD: 0000-0002-4954-926X
Department of Biology, Clemson University, United States .
Marine Science Institute, University of Texas at Austin, United States .
Marine Science Institute, University of Texas at Austin, United States .
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2014 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 155, no 11, 4237-4249 p.Article in journal (Refereed) Published
Abstract [en]

Rapid, cell surface-initiated, pregenomic androgen actions have been described in various vertebrate cells, but the receptors mediating these actions remain unidentified.We report here cloning and expression of a cDNA from Atlantic croaker (Micropogonias undulatus) ovaries encoding a 33kDa, 7-transmembrane protein with binding and signaling characteristics of a membrane androgen receptor (mAR) that is unrelated to any previously described steroid receptor. Instead croaker mAR has 81–93 % amino acid sequence identity with zinc transporter ZIP9 (SLC39A9) subfamily members, indicating it is a ZIP9 protein. Croaker ZIP9 is expressed in gonadal tissues and in brain, and is upregulated in the ovary by reproductive hormones. ZIP9 protein is localized to plasma membranes of croaker granulosa cells and human breast cancer (SKBR-3) cells stably transfected with ZIP9. Recombinant croaker ZIP9 has a high affinity (Kd 12.7 nM), limited capacity (Bmax 2.8nM/mgprotein), displaceable, single binding site specific for androgens, characteristic of steroid receptors. Testosterone activates a stimulatory G protein coupled to ZIP9, resulting in increased cAMP production. Testosterone promotes serum starvation-induced cell death and apoptosis in transfected cells and in croaker ovarian follicle cells that is associated with rapid increases in intracellular free zinc concentrations, suggesting an involvement of zinc in this nonclassical androgen action to promote apoptosis. These responses to testosterone are abrogated by treatment with ZIP9 siRNA. The results provide the first evidence that zinc transporter proteins can function as specific steroid membrane receptors and indicate a previously unrecognized signaling pathway mediated by steroid receptors involving alterations in intracellular zinc.

Place, publisher, year, edition, pages
2014. Vol. 155, no 11, 4237-4249 p.
National Category
Biological Sciences
Research subject
Biology
Identifiers
URN: urn:nbn:se:oru:diva-35903DOI: 10.1210/en.2014-1198ISI: 000343422800015Scopus ID: 2-s2.0-84908032921OAI: oai:DiVA.org:oru-35903DiVA: diva2:736957
Note

Funding Agency:

National Institutes of Health ESO 12961

Available from: 2014-08-11 Created: 2014-08-11 Last updated: 2017-10-17Bibliographically approved

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