Marked Disturbance of Calcium Homeostasis in Mice With Targeted Disruption of the <i>Trpv6</i> Calcium Channel Gene

Bianco, Suzy D.C.; Ji, Peng; Takanaga, Hitomi; Suzuki, Yoshiro; Crescenzi, Alessandra; Kos, Claudine H.; Zhuang, Liyan; Freeman, Michael R.; Gouveia, Cecília Helena de Azevedo; Wu, Jiangping; Luo, Hongyu; Mauro, Theodora M.; Brown, Edward M.; Hediger, Matthias A.

doi:10.1359/jbmr.061110

Cited by 261 publications

(239 citation statements)

References 40 publications

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“…The strain of TRPV6 ϩ/Ϫ heterozygote mice was received from the Laboratory of Professor M. Hediger (23). The TRPV6 KO mice were generated 2D3 or 700 ng E analog per kg of body weight.…”

Section: Methodsmentioning

confidence: 99%

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TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo

Kutuzova

Sundersingh

Vaughan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The requirement for TRPV6 for vitamin D-dependent intestinal calcium absorption in vivo has been examined by using vitamin D-deficient TRPV6 null mice and littermate wild-type mice. Each of the vitamin D-deficient animals received each day for 4 days 50 ng of 1,25-dihydroyvitamin D 3 in 0.1 ml of 95% propylene glycol:5% ethanol vehicle or vehicle only. Both the wild-type and TRPV6 null mice responded equally well to 1,25-dihydroxyvitamin D 3 in increasing intestinal calcium absorption. These results, along with our microarray data, demonstrate that TRPV6 is not required for vitamin D-induced intestinal calcium absorption and may not carry out a significant role in this process. These and previous results using calbindin D9k null mutant mice illustrate that molecular events in the intestinal calcium absorption process in response to the active form of vitamin D remain to be defined.A primary function of vitamin D is to markedly increase intestinal absorption of calcium and phosphate (1). During the 1950s, this absorption was shown to be primarily an active calcium transport process and an independent active phosphate transport process (2, 3). With the discovery of the vitamin D endocrine system came the understanding that this process was directly stimulated by the hormonal form of vitamin D, 1␣,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) (4). Because this hormonal form of vitamin D is regulated in response to the need for calcium, it became clear that the endogenous factor discovered by Nicolaysen and Egg-Larsen is the vitamin D endocrine system producing the final vitamin D hormone, 1,25-(OH) 2 D 3 (4, 5). There is still debate whether vitamin D further influences the diffusional component of calcium absorption, taking place at high intestinal levels of calcium (6, 7).The molecular mechanism underlying active calcium transport in response to vitamin D began unraveling with the discovery of calbindin D 9k by Wasserman and colleagues (8). Schachter and colleagues (9) also found a transporter responsive to vitamin D. Others have reported that vitamin D stimulates the basal lateral membrane calcium ATPase believed to be a calcium transporter (10, 11). These components have been put together in a diagrammatic fashion to present the current hypothesis of how 1,25-(OH) 2 D 3 stimulates active intestinal calcium absorption. TRPV6 is a calcium channel protein clearly induced by 1,25-(OH) 2 D 3 (12). Calcium entering through this channel is believed to associate with calbindin D 9k , which serves as a shuttle for calcium, presenting it to the basal lateral membrane calcium ATPase. This step provides the energy input for the transfer of calcium against a concentration gradient. All three of these genes are clearly under the influence of the active form of vitamin D (13). Unfortunately not all evidence is currently in support of this hypothesis. Transgenic mice in which calbindin D 9k has been eliminated have shown that calbindin D 9k is not required for 1,25-(OH) 2 D 3 -stimulated intestinal calcium absorption (14, 15). Fo...

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“…The strain of TRPV6 ϩ/Ϫ heterozygote mice was received from the Laboratory of Professor M. Hediger (23). The TRPV6 KO mice were generated 2D3 or 700 ng E analog per kg of body weight.…”

Section: Methodsmentioning

confidence: 99%

“…as described by Bianco et al and had B6/129 background (23). The TRPV6 KO mice were backcrossed with the C57/B6 mice for three generations and were still carrying a mixed background of B6/129.…”

Section: Methodsmentioning

confidence: 99%

TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo

Kutuzova

Sundersingh

Vaughan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…TRPV6 mRNA expression is regulated by dietary calcium, 1,25-vitamin D3, dihydrotestosterone, and estrogen (20)(21)(22). The intestinal calcium absorption is significantly reduced in TRPV6 knockout mice (23). This shows the importance of TRPV6 as a major calcium uptake pathway of dietary calcium in the intestine.…”

Section: Introductionmentioning

confidence: 92%

Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Bolanz

Kovács

Landowski

et al. 2009

Molecular Cancer Research

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The epithelial calcium channel TRPV6 is upregulated in breast carcinoma compared with normal mammary gland tissue. The selective estrogen receptor modulator tamoxifen is widely used in breast cancer therapy. Previously, we showed that tamoxifen inhibits calcium uptake in TRPV6-transfected Xenopus oocytes. In this study, we examined the effect of tamoxifen on TRPV6 function and intracellular calcium homeostasis in MCF-7 breast cancer cells transiently transfected with EYFP-C1-TRPV6. TRPV6 activity was measured with fluorescence microscopy using Fura-2. The basal calcium level was higher in transfected cells compared with nontransfected cells in calcium-containing solution but not in nominally calcium-free buffer. Basal influxes of calcium and barium were also increased. In transfected cells, 10 μmol/L tamoxifen reduced the basal intracellular calcium concentration to the basal calcium level of nontransfected cells. Tamoxifen decreased the transport rates of calcium and barium in transfected cells by 50%. This inhibitory effect was not blocked by the estrogen receptor antagonist, ICI 182,720. Similarly, a tamoxifen-induced inhibitory effect was also observed in MDA-MB-231 estrogen receptor-negative cells. The effect of tamoxifen was completely blocked by activation of protein kinase C. Inhibiting protein kinase C with calphostin C decreased TRPV6 activity but did not alter the effect of tamoxifen. These findings illustrate how tamoxifen might be effective in estrogen receptor-negative breast carcinomas and suggest that the therapeutic effect of tamoxifen and protein kinase C inhibitors used in breast cancer therapy might involve TRPV6-mediated calcium entry. This study highlights a possible role of TRPV6 as therapeutic target in breast cancer therapy.

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“…TRPV6 expression is upregulated in the presence of increased levels of extracellular Ca 2+ and mediates Ca 2+ influx, leading to increased cytoplasmic Ca 2+ levels in human keratinocytes, whereas knockdown of TRPV6 in human keratinocytes impairs differentiation in vitro (Lehen'kyi et al, 2007). In addition, TRPV6 knockout mice exhibit impaired stratum corneum formation that is associated with a decrease in epidermal Ca 2+ content (Bianco et al, 2007). Furthermore, it has been shown that 1,25-dihydroxyvitamin D3, a key regulator of keratinocyte differentiation, regulates the uptake of Ca 2+ by TRPV6 in human keratinocytes (Lehen'kyi et al, 2007).…”

Section: Trpv Channelsmentioning

confidence: 99%

Defective channels lead to an impaired skin barrier

Blaydon¹,

Kelsell²

2014

Journal of Cell Science

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Channels are integral membrane proteins that form a pore, allowing the passive movement of ions or molecules across a membrane (along a gradient), either between compartments within a cell, between intracellular and extracellular environments or between adjacent cells. The ability of cells to communicate with one another and with their environment is a crucial part of the normal physiology of a tissue that allows it to carry out its function. Cell communication is particularly important during keratinocyte differentiation and formation of the skin barrier. Keratinocytes in the skin epidermis undergo a programme of apoptosis-driven terminal differentiation, whereby proliferating keratinocytes in the basal (deepest) layer of the epidermis stop proliferating, exit the basal layer and move up through the spinous and granular layers of the epidermis to form the stratum corneum, the external barrier. Genes encoding different families of channel proteins have been found to harbour mutations linked to a variety of rare inherited monogenic skin diseases. In this Commentary, we discuss how human genetic findings in aquaporin (AQP) and transient receptor potential (TRP) channels reveal different mechanisms by which these channel proteins function to ensure the proper formation and maintenance of the skin barrier.

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Marked Disturbance of Calcium Homeostasis in Mice With Targeted Disruption of the Trpv6 Calcium Channel Gene

Cited by 261 publications

References 40 publications

TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo

TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo

Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Defective channels lead to an impaired skin barrier

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Marked Disturbance of Calcium Homeostasis in Mice With Targeted Disruption of the Trpv6 Calcium Channel Gene

Cited by 261 publications

References 40 publications

TRPV6 is not required for 1α,25-dihydroxyvitamin D 3 -induced intestinal calcium absorption in vivo

TRPV6 is not required for 1α,25-dihydroxyvitamin D 3 -induced intestinal calcium absorption in vivo

Tamoxifen Inhibits TRPV6 Activity via Estrogen Receptor–Independent Pathways in TRPV6-Expressing MCF-7 Breast Cancer Cells

Defective channels lead to an impaired skin barrier

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TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo

TRPV6 is not required for 1α,25-dihydroxyvitamin D ₃ -induced intestinal calcium absorption in vivo