Cellular uptake of steroid carrier proteins—Mechanisms and implications

Willnow, Thomas E.; Nykjaer, Anders

doi:10.1016/j.mce.2009.07.021

Cited by 66 publications

(44 citation statements)

References 125 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This luminal ligand uptake may not only concern corticosteroids that were freely filtered at the glomeruli but also those that were filtered bound to plasma proteins. In fact, there is increasing evidence that steroid hormones may enter certain cell types not only by free diffusion but also by receptor-mediated endocytosis of their carrier proteins (59). Notably, circulating corticosteroids are bound Ͼ90% to corticosteroid-binding globulin (CBG), which has a molecular mass of 55 kDa (27), which is just below the 60 kDa cut-off of the glomerular filter.…”

Section: Discussionmentioning

confidence: 99%

In vivo nuclear translocation of mineralocorticoid and glucocorticoid receptors in rat kidney: differential effect of corticosteroids along the distal tubule

Ackermann

Gresko

Carrel

et al. 2010

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Aldosterone and corticosterone bind to mineralocorticoid (MR) and glucocorticoid receptors (GR), which, upon ligand binding, are thought to translocate to the cell nucleus to act as transcription factors. Mineralocorticoid selectivity is achieved by the 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) that inactivates 11β-hydroxy glucocorticoids. High expression levels of 11β-HSD2 characterize the aldosterone-sensitive distal nephron (ASDN), which comprises the segment-specific cells of late distal convoluted tubule (DCT2), connecting tubule (CNT), and collecting duct (CD). We used MR- and GR-specific antibodies to study localization and regulation of MR and GR in kidneys of rats with altered plasma aldosterone and corticosterone levels. In control rats, MR and GR were found in cell nuclei of thick ascending limb (TAL), DCT, CNT, CD cells, and intercalated cells (IC). GR was also abundant in cell nuclei and the subapical compartment of proximal tubule (PT) cells. Dietary NaCl loading, which lowers plasma aldosterone, caused a selective removal of GR from cell nuclei of 11β-HSD2-positive ASDN. The nuclear localization of MR was unaffected. Adrenalectomy (ADX) resulted in removal of MR and GR from the cell nuclei of all epithelial cells. Aldosterone replacement rapidly relocated the receptors in the cell nuclei. In ASDN cells, low-dose corticosterone replacement caused nuclear localization of MR, but not of GR. The GR was redistributed to the nucleus only in PT, TAL, early DCT, and IC that express no or very little 11β-HSD2. In ASDN cells, nuclear GR localization was only achieved when corticosterone was replaced at high doses. Thus ligand-induced nuclear translocation of MR and GR are part of MR and GR regulation in the kidney and show remarkable segment- and cell type-specific characteristics. Differential regulation of MR and GR may alter the level of heterodimerization of the receptors and hence may contribute to the complexity of corticosteroid effects on ASDN function.

show abstract

Section: Discussionmentioning

confidence: 99%

In vivo nuclear translocation of mineralocorticoid and glucocorticoid receptors in rat kidney: differential effect of corticosteroids along the distal tubule

Ackermann

Gresko

Carrel

et al. 2010

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…Cubulin, a second surface receptor for DBP in the proximal tubule, also associates with megalin to internalize complexes of DBP and 25(OH)D 3 (337). In addition, disabled 2 (Dab) 2, a cytoplasmic adaptor protein, also works in conjunction with megalin for the cellular uptake of DBP/25(OH)D 3 by binding to the cytoplasmic tail of megalin enabling the proper routing of the receptor (320,490).…”

Section: A Vitamin D and 25(oh)dmentioning

confidence: 99%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,422

1,234

View full text Add to dashboard Cite

, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

show abstract

“…In contrast to free steroids, commonly considered to freely distribute in tissues by passive diffusion (Mendel 1989, Willnow & Nykjaer 2010, the transport of the substantially more polar sulfated steroids across the membrane obviously depends on more-or less-specific transport mechanisms. Thus, the cellular import or export of sulfated steroids may provide mechanisms for their directed transport within and between tissues.…”

Section: Introductionmentioning

confidence: 99%

Free and sulfated steroids secretion in postpubertal boars (Sus scrofa domestica)

et al. 2014

View full text Add to dashboard Cite

Sulfated steroids have been traditionally regarded as inactive metabolites. However, they may also serve as precursors for the production of active free steroids in target cells. In this study, we used the boar as a model to study the metabolism, transport, and function of steroid sulfates due to their high production in the porcine testicular-epididymal compartment, of which the role is unknown. To characterize the secretion of free and sulfated steroids, plasma samples were collected from six postpubertal boars over 6 h every 20 min from the jugular vein. Long-term secretion profiles were also established in seven boars stimulated with human chorionic gonadotropin. To directly characterize the testicular output, samples were collected from superficial testicular arterial and venous blood vessels. Testosterone, androstenedione and sulfated pregnenolone, DHEA, estrone (E 1 ), and estradiol-17b (E 2 ) were determined by liquid chromatography-tandem mass spectrometry. Free E 1 and E 2 were measured by RIA. Irrespective of a high variability between individuals, the results suggest that i) all steroids assessed are primarily produced in the testis, ii) they exhibit similar profiles pointing to a pulsatile secretion with low frequency (three to five pulses per day), and iii) after synthesis at least a major proportion is immediately released into peripheral circulation. The fact that all steroid sulfates assessed are original testicular products and their high correlations with one another suggest their role as being intermediates of testicular steroidogenesis rather than as being inactivated end products. Moreover, a substantial use of sulfated steroids in porcine testicular steroidogenesis would assign a crucial regulatory role to steroid sulfatase, which is highly expressed in Leydig cells.

show abstract

Cellular uptake of steroid carrier proteins—Mechanisms and implications

Cited by 66 publications

References 125 publications

In vivo nuclear translocation of mineralocorticoid and glucocorticoid receptors in rat kidney: differential effect of corticosteroids along the distal tubule

In vivo nuclear translocation of mineralocorticoid and glucocorticoid receptors in rat kidney: differential effect of corticosteroids along the distal tubule

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Free and sulfated steroids secretion in postpubertal boars (Sus scrofa domestica)

Contact Info

Product

Resources

About