Calcium Channel TRPV6 Is Involved in Murine Maternal–Fetal Calcium Transport

Suzuki, Yoshiro; Kovacs, Christopher S.; Takanaga, Hitomi; Peng, Ji‐Bin; Landowski, Christopher P.; Hediger, Matthias A.

doi:10.1359/jbmr.080314

Cited by 100 publications

(81 citation statements)

References 31 publications

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“…β-actin, used as a loading control, demonstrated equal loading between groups. Placental TRPV6 expression, recently shown to be important in maternofetal calcium transport (29), was not different between P0 and WT at either E17 or E19. In contrast, calbindin-D 9K expression was significantly lower in P0 placentas compared to WT at E17 (P < 0.01), with this trend observed in all eight litters.…”

Section: Resultsmentioning

confidence: 70%

Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

Dilworth¹,

Kusinski²,

Cowley³

et al. 2010

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

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Evidence is emerging that the ability of the placenta to supply nutrients to the developing fetus adapts according to fetal demand. To examine this adaptation further, we tested the hypothesis that placental maternofetal transport of calcium adapts according to fetal calcium requirements. We used a mouse model of fetal growth restriction, the placental-specific Igf2 knockout (P0) mouse, shown previously to transiently adapt placental System-A amino acid transporter activity relative to fetal growth. Fetal and placental weights in P0 mice were reduced when compared with WT at both embryonic day 17 (E17) and E19. Ionized calcium concentration [Ca 2+ ] was significantly lower in P0 fetal blood compared with both WT and maternal blood at E17 and E19, reflecting a reversal of the fetomaternal [Ca 2+ ] gradient. Fetal calcium content was reduced in P0 mice at E17 but not at E19. Unidirectional maternofetal calcium clearance ( Ca K mf ) was not different between WT and P0 at E17 but increased in P0 at E19. Expression of the intracellular calcium-binding protein calbindin-D 9K , previously shown to be rate-limiting for calcium transport, was increased in P0 relative to WT placentas between E17 and E19. These data show an increased placental transport of calcium from E17 to E19 in P0 compared to WT. We suggest that this is an adaptation in response to the reduced fetal calcium accumulation earlier in gestation and speculate that the ability of the placenta to adapt its supply capacity according to fetal demand may stretch across other essential nutrients.fetal growth restriction | calbindin | PMCA | pregnancy

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Section: Resultsmentioning

confidence: 70%

Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

Dilworth¹,

Kusinski²,

Cowley³

et al. 2010

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

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“…The robust maintenance of this "fetal hypercalcemia" across numerous mammalian species suggests that it is physiologically important. But fetal hypocalcemia does not impair survival to the end of gestation, as shown by study of Pthrp null, Pth1r null, Hoxa3 null, Trpv6 null, Gp130 null, and Pthrp/Hoxa3 double mutant fetuses (336,339,341,616,659). Another possibility is that a high blood calcium level in utero may improve survival after birth.…”

Section: Animal Datamentioning

confidence: 98%

“…Gated calcium channels [such as transient receptor potential cation channel, subfamily V, member 6 (TRPV6)] open within maternal-facing basement membranes to allow calcium entry into the relevant cells, calcium then shuttles to the opposite basement membrane bound to binding proteins, and then Ca 2ϩ -ATPase at the fetal-facing basement membranes actively pumps calcium into the fetal circulation (95,659). The relevant calcium transporting cells are the trophoblasts and probably the intraplacental yolk sac cells within rodent placentas (63,188,337).…”

Section: Overview Of Mechanismsmentioning

confidence: 99%

“…It is expressed as early as day 10 of gestation in rodent placentas (607), and its expression increases markedly over the last week of gestation in rats (81,151,227) and mice (150,659). Other calcium binding proteins are also expressed within trophoblasts and intraplacental yolk sac cells and show increased expression over the same interval (251,252,692).…”

Section: Overview Of Mechanismsmentioning

confidence: 99%

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Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

Kovacs

2014

Physiological Reviews

207

188

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Mineral and bone metabolism are regulated differently in utero compared with the adult. The fetal kidneys, intestines, and skeleton are not dominant sources of mineral supply for the fetus. Instead, the placenta meets the fetal need for mineral by actively transporting calcium, phosphorus, and magnesium from the maternal circulation. These minerals are maintained in the fetal circulation at higher concentrations than in the mother and normal adult, and such high levels appear necessary for the developing skeleton to accrete a normal amount of mineral by term. Parathyroid hormone (PTH) and calcitriol circulate at low concentrations in the fetal circulation. Fetal bone development and the regulation of serum minerals are critically dependent on PTH and PTH-related protein, but not vitamin D/calcitriol, fibroblast growth factor-23, calcitonin, or the sex steroids. After birth, the serum calcium falls and phosphorus rises before gradually reaching adult values over the subsequent 24 -48 h. The intestines are the main source of mineral for the neonate, while the kidneys reabsorb mineral, and bone turnover contributes mineral to the circulation. This switch in the regulation of mineral homeostasis is triggered by loss of the placenta and a postnatal fall in serum calcium, and is followed in sequence by a rise in PTH and then an increase in calcitriol. Intestinal calcium absorption is initially a passive process facilitated by lactose, but later becomes active and calcitriol-dependent. However, calcitriol's role can be bypassed by increasing the calcium content of the diet, or by parenteral administration of calcium.

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“…TRPV5 knockout mice exhibit a 6-to 10-fold increase in urinary Ca 2ϩ excretion (26); and TRPV6 knockout mice show a 60% reduction in intestinal and a 40% reduction in placental calcium transport (3,52). To keep up with the body's need for Ca 2ϩ , TRPV5/6-mediated Ca 2ϩ transport is under vigorous regulation.…”

mentioning

confidence: 99%

WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway

Zhang

Na²,

Peng³

2008

American Journal of Physiology-Renal Physiology

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Zhang W, Na T, Peng J-B. WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway. Am J Physiol Renal Physiol 295: F1472-F1484, 2008. First published September 3, 2008 doi:10.1152/ajprenal.90229.2008 absorption. The kinase domain of WNK3 alone was sufficient to increase TRPV5-mediated Ca 2ϩ transport, and the positive regulatory effect was abolished by the kinase-inactive D294A mutation in WNK3, indicating a kinase-dependent mechanism. The complexly glycosylated TRPV5 that appears at the plasma membrane was increased by WNK3. The exocytosis of TRPV5 was increased by WNK3, and the effect of WNK3 on TRPV5 was abolished by the microtubule inhibitor colchicine. The increased plasma membrane expression of TRPV5 was likely due to the enhanced delivery of mature TRPV5 to the plasma membrane from its intracellular pool via the secretory pathway. These results indicate that WNK3 is a positive regulator of the transcellular Ca 2ϩ transport pathway. While clinical manifestations such as hyperkalemia, hypertension, mild metabolic acidosis, low renin, and normal glomerular filtration rate are commonly present in FHH (23), patients with Q565E mutation in WNK4 also exhibit hypercalciuria and hypersensitivity to thiazide diuretics (37, 38), whereas patients with WNK1 mutation do not show urinary calcium wasting (1). The nature of electrolyte imbalance in FHH motivated the studies on the effects of WNKs on ion transport proteins. WNK4 was shown to inhibit the thiazide-sensitive Na-Cl cotransporter (NCC) (5,21,22,61,(67)(68)(69) and other members of the SLC12A family (20, 28), the renal outer medullary K ϩ channel (ROMK) (24,31,50), the epithelial sodium channel (ENaC) (16,49,50), and osmolarity-sensitive calcium-permeable channel TRPV4 (17), and to enhance epithelial calcium channel TRPV5 (27). WNK1, on the other hand, regulates ENaC (41,64,65) and ROMK (11,33,59) in a manner independent of its kinase activity. In addition, WNK4 and WNK1 also regulate paracellular Cl Ϫ permeability through regulating the claudins (29,42,66). Both WNK1 and WNK4 can also regulate SLC12A members through the activation of STE20 kinases (2,18,40,57,58). Misregulation of NCC by WNK4 mutants was confirmed in transgenic mouse studies and is most relevant to the pathogenesis of FHH (32, 70). WNK3 has been shown to be a potent regulator of the SLC12A family of electroneutral cation/Cl Ϫ cotransporters in a kinase-dependent manner (12,30,47,48). In contrast to the effects of WNK3 on SLC12A family members, WNK3 decreases the plasma membrane expression of ROMK1 independent of its kinase activity (34). Similarly, the Cl Ϫ channel SLC26A9 is also inhibited by WNK3 in a kinase-independent manner (14).TRPV5 and TRPV6 are Ca 2ϩ -selective channels, which mediated the apical Ca 2ϩ entry process of the transcellular calcium transport pathway in the kidney and intestine, respectively (25, 45). TRPV5 knockout mice exhibit a 6-to 10-fold increase in urinary Ca 2ϩ excretion (26); and TRPV6 knockout mice show a 60% reduction ...

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Calcium Channel TRPV6 Is Involved in Murine Maternal–Fetal Calcium Transport

Cited by 100 publications

References 31 publications

Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

Bone Development and Mineral Homeostasis in the Fetus and Neonate: Roles of the Calciotropic and Phosphotropic Hormones

WNK3 positively regulates epithelial calcium channels TRPV5 and TRPV6 via a kinase-dependent pathway

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