ZIP9, a novel membrane androgen receptor and zinc transporter protein

Thomas, Peter; Converse, Aubrey; Berg, André

doi:10.1016/j.ygcen.2017.04.016

Cited by 92 publications

(69 citation statements)

References 56 publications

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“…On the other hand, several authors demonstrated that the use of the AR antagonist (flutamide) [19][20][21], albumin-bound androgen analogues, which cannot pass through the membrane [19] and protein synthesis inhibitors [22] are not involved in T vasodilator effect. Besides, some authors also observed that T induced vasodilation in arteries without the nuclear functional AR [20,23,24], thereby demonstrating that this effect was not mediated by AR [20]. Several hypotheses have been proposed to explain the rapid androgens' vascular responses, namely a steroid nuclear receptor translocation to the cell membrane surface, nonspecific effects of steroids on plasma membrane fluidity or direct allosteric modification of ion channels dependent of binders and G protein-coupled receptors (GPRCs) [25].…”

Section: Genomic and Non-genomic Overlapping Vasodilatory Mechanisms mentioning

confidence: 99%

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Vascular Pathways of Testosterone: Clinical Implications

Lorigo

Mariana

Oliveira

et al. 2019

J. of Cardiovasc. Trans. Res.

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Cardiovascular diseases (CVD) are one of the leading causes of death worldwide. Testosterone (T) is an important sex hormone that triggers several genomic and non-genomic pathways, leading to improvements of several cardiovascular risk factors and quality of life in men. At the vascular level, the key effect of T is the vasorelaxation. This review discusses the molecular pathways and clinical implications of T in the vascular system. Firstly, the mechanisms involved in the T vasodilator effect will be presented. Then, it will be discussed the association of T with the main risks for CVD, namely metabolic syndrome, type 2 diabetes mellitus, obesity, atherosclerosis, dyslipidaemia and hypertension. Several studies have shown a correlation between low T levels and an increased prevalence of several CVD. These observations suggest that T has beneficial effects on the cardiovascular system and that testosterone replacement therapy may become a therapeutic reality for some of these disorders.

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Section: Genomic and Non-genomic Overlapping Vasodilatory Mechanisms mentioning

confidence: 99%

“…Recently, four new membrane AR have been suggested to be responsible for the non-genomic effects of androgens. Two of them are GPCR (OXER1 and GPR6A) and the other ion channels/ transporters for calcium and zinc (TRPM8 and ZIP9) respectively [23,24].…”

Section: Genomic and Non-genomic Overlapping Vasodilatory Mechanisms mentioning

confidence: 99%

Vascular Pathways of Testosterone: Clinical Implications

Lorigo

Mariana

Oliveira

et al. 2019

J. of Cardiovasc. Trans. Res.

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“…ZIP9 is the only member of the ZIP subfamily I, and is an androgen receptor, coupled to G proteins . Human ZIP9 has been localized to the trans Golgi network (TGN) in transfected HeLa cells in a zinc‐independent manner .…”

Section: Subfamily Imentioning

confidence: 99%

The trafficking of metal ion transporters of the Zrt‐ and Irt‐like protein family

Bowers

Srai

2018

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Metal ion transporters of the Zrt- and Irt-like protein (ZIP, or SLC39A) family transport zinc, iron, manganese and/or cadmium across cellular membranes and into the cytosol. The 14 human ZIP family proteins are expressed in a wide variety of tissues and function in many different cellular processes. Many of these proteins (including ZIP1, 2, 3, 4, 5, 6/10, 8, 9, 11, 12, 14) are situated, at least some of the time, on the plasma membrane, where they mediate metal ion uptake into cells. Their level on the cell surface can be controlled rapidly via protein trafficking in response to the ions they transport. For example, the cell surface level of many ZIPs (including ZIP1, 3, 4, 8 and 12) is mediated by the available concentration of zinc. Zinc depletion causes a decrease in endocytosis and degradation, resulting in more ZIP on the surface to take up the essential ion. ZIP levels on the cell surface are a balance between endocytosis, recycling and degradation. We review the trafficking mechanisms of human ZIP proteins, highlighting possible targeting motifs and suggesting a model of zinc-mediated endocytic trafficking. We also provide two possible models for ZIP14 trafficking and degradation.

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“…Genetic evidence using a zebrafish ar mutant confirmed that this was indeed via AR-independent signalling. Potential candidates for this non-canonical pathway include GPRC6A 64 , ZIP9 65,66 , OXER1 67 and L-type calcium channels (LTCCs) [39][40][41][42][43] . Testosterone has been shown to bind to these receptors, mediating non-genomic activity which is independent of AR ( Fig.…”

Section: Discussionmentioning

confidence: 99%

A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2−/− phenotype

Metzner

Griffiths

Streets

et al. 2020

Sci Rep

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Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of end-stage renal failure in humans and results from germline mutations in PKD1 or PKD2. Despite the recent approval of tolvaptan, safer and more effective alternative drugs are clearly needed to slow disease progression. As a first step in drug discovery, we conducted an unbiased chemical screen on zebrafish pkd2 mutant embryos using two publicly available compound libraries (Spectrum, PKIS) totalling 2,367 compounds to identify novel treatments for ADPKD. Using dorsal tail curvature as the assay readout, three major chemical classes (steroids, coumarins, flavonoids) were identified from the Spectrum library as the most promising candidates to be tested on human PKD1 cystic cells. Amongst these were an androgen, 5α−androstane 3,17-dione, detected as the strongest enhancer of the pkd2 phenotype but whose effect was found to be independent of the canonical androgen receptor pathway. From the PKIS library, we identified several ALK5 kinase inhibitors as strong suppressors of the pkd2 tail phenotype and in vitro cyst expansion. In summary, our results identify ALK5 and non-canonical androgen receptors as potential therapeutic targets for further evaluation in drug development for ADPKD.

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ZIP9, a novel membrane androgen receptor and zinc transporter protein

Cited by 92 publications

References 56 publications

Vascular Pathways of Testosterone: Clinical Implications

Vascular Pathways of Testosterone: Clinical Implications

The trafficking of metal ion transporters of the Zrt‐ and Irt‐like protein family

A high throughput zebrafish chemical screen reveals ALK5 and non-canonical androgen signalling as modulators of the pkd2−/− phenotype

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