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This Article Full Text (PDF) All Versions of this Article: ASN.2006080935v1 17/11/2954    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schlatter, E. Search for Related Content PubMed PubMed Citation Articles by Schlatter, E. Related Collections Related Article

Who Wins the Competition: TRPV5 or Calbindin-D_28K?

Universitatsklinikum Münster, Medizinische Klinik und Poliklinik D, Münster, Germany

Address correspondence to: Dr. Eberhard Schlatter, Universitatsklinikum Münster, Medizinische Klinik und Poliklinik D, Experimentelle Nephrologie, Domagkstrasse 3a, 48149 Münster, Germany. Phone: +49-251-83-56991; Fax: +49-251-83-56973; E-mail: eberhard.schlatter{at}uni-muenster.de

The calcium ion (Ca²⁺) is essential to the normal function of all living cells. Numerous hereditary and clinical disorders directly result from dysregulation of the body Ca²⁺ balance. In human, 99% of total body Ca²⁺ resides in the skeleton, and 1% is distributed in the soft tissues and extracellular fluids. The concentration of Ca²⁺ in the cytoplasm and in the extracellular fluid is rigidly maintained, in line with the critical physiologic importance of Ca²⁺ to a wide variety of biologic processes. To study the molecular mechanism in maintaining the extracellular Ca²⁺ balance, several investigators are now applying the powerful tools of transgenic technology to better understand how a gene contributes to the Ca²⁺ balance or may cause a human disease. In this issue of JASN, Gkika and co-workers reported the phenotype of the transient receptor potential vanilloid member 5 (TRPV5) and calbindin-D_28K double-knockout mice and further explored the relationship between TRPV5 and calbindin-D_28K, two key molecules in renal Ca²⁺ handling (1).

In the kidney, Ca²⁺ can re-enter the circulation by paracellular (passive) as well as transcellular (active) Ca²⁺ reabsorption, which is the main target for the calciotropic hormones. Active Ca²⁺ reabsorption comprises a sequence of processes restricted to the distal convoluted tubule (DCT) and the connecting tubule (CNT) (2). At the cellular level, transcellular reabsorption is mediated by Ca²⁺ entry across the apical membrane through the specialized epithelial Ca²⁺ channel, TRPV5, intracellular buffering of Ca²⁺ and facilitated diffusion of Ca²⁺ bound to Ca²⁺-binding proteins (calbindins), and finally Ca²⁺ extrusion across the basolateral membrane by a Na⁺/Ca²⁺ exchanger (NCX1) and a plasma membrane Ca²⁺-ATPase (PMCA1b) (Figure 1) (2). In the intestine, a similar mechanism for transcellular Ca²⁺ absorption occurs with TRPV6 as the gatekeeper, calbindin-D_9K as intracellular ferry of Ca²⁺, and PMCA1b as the extrusion mechanism.

View larger version (61K): [in this window] [in a new window] [as a PowerPoint slide]   Figure 1. Mechanism of epithelial Ca2+ transport. Epithelia can absorb Ca2+ by paracellular and transcellular transport. Passive and paracellular Ca2+ transport takes place across the tight junctions and is driven by the electrochemical gradient for Ca2+ (blue arrow). The active form of vitamin D (1,25-(OH)2D3) stimulates the individual steps of transcellular Ca2+ transport by increasing the expression levels of the luminal Ca2+ channels, calbindins, and the extrusion systems. Active and transcellular Ca2+ transport is carried out as a three-step process. After entry of Ca2+ through the (hetero)tetrameric epithelial Ca2+ channels, TRPV5 and TRPV6, Ca2+ bound to calbindin diffuses to the basolateral membrane. At the basolateral membrane, Ca2+ is extruded via an ATP-dependent Ca2+-ATPase (PMCA1b) and a Na+/Ca2+ exchanger (NCX1). In this way, there is net Ca2+ absorption from the luminal space to the extracellular compartment.

Calbindin-D_28K, the main Ca²⁺-binding protein in DCT and CNT, facilitates Ca²⁺ diffusion and lowers the intracellular Ca²⁺ concentration to avoid Ca²⁺ toxicity. Although several studies suggested a crucial role for calbindin-D_28k in the process of active renal Ca²⁺ reabsorption, calbindin-D_28K knockout (calbindin-D_28K^–/–) mice exhibit a normal Ca²⁺ balance or mild hypercalciuria, depending on the Ca²⁺ diet, in contrast to TRPV5^–/– mice, which show profound hypercalciuria, compensatory intestinal Ca²⁺ hyperabsorption, and reduced bone thickness (9). In this issue of JASN, Gkika et al. investigated whether calbindin-D_28K deficiency is critical for active Ca²⁺ reabsorption in the presence or absence of TRPV5 (1). To study this question, single- and double-knockout mice of TRPV5 and calbindin-D_28K (TRPV5^–/–, calbindin-D_28K^–/–, and TRPV5^–/–/calbindin-D_28K^–/–) were generated. These mice strains were characterized for the amount of Ca²⁺ excreted in the urine, intestinal Ca²⁺ absorption, plasma PTH, and 1,25(OH)₂D₃ levels, as well as expression levels of Ca²⁺ transporter proteins. Interestingly, TRPV5^–/–/calbindin-D_28K^–/– mice displayed prominent Ca²⁺ abnormalities similar to the TRPV5^–/– mice, such as hypercalciuria and increased Ca²⁺ absorption, whereas calbindin-D_28K^–/– mice showed a wild-type phenotype. These findings suggest that TRPV5 but not calbindin-D_28K may be the critical component in renal active Ca²⁺ reabsorption.

At the cellular level, a recent study demonstrated that calbindin-D_28k dynamically controls TRPV5-mediated Ca²⁺ influx by physical interaction with the channel at the plasma membrane. Lambers et al. applied evanescent-field microscopy and subcellular fractionation studies and found that calbindin-D_28k translocates toward to the plasma membrane, where it directly associates with TRPV5 at a low intracellular Ca²⁺ concentration (10). Here, it buffers Ca²⁺ that enters the renal epithelial cell, thereby counteracting local accumulation of cytosolic-free Ca²⁺ and coherent inactivation of the channel. Upon Ca²⁺ binding, calbindin-D_28K diffuses from TRPV5 and facilitates transport of Ca²⁺ to the basolateral membrane. These data suggest that calbindin-D_28k acts as a dynamic Ca²⁺ buffer, regulating Ca²⁺ concentration by coordination of TRPV5. Calbindin-D_28K and TRPV5 apparently form a functional protein couple essential for renal Ca²⁺ handling. However, gene-ablation of calbindin-D_28k in mice did not affect renal Ca²⁺ handling. Other unknown Ca²⁺-binding proteins that substitute the function in calbindin-D_28K^–/– mice can possibly compensate the calbindin-D_28K deficiency. Interestingly, the specific co-expression of calbindin-D_9K and calbindin-D_28K in mouse DCT cells hints to a comparable function of calbindin-D_9K in Ca²⁺ reabsorption. Recently, Kutuzova and co-workers showed that calbindin-D_9K knockout mice do not exhibit any overt phenotypic abnormalities. These mice are able to maintain normal plasma Ca²⁺ levels; however, Ca²⁺ absorption and urinary Ca²⁺ excretion have not yet been examined (11). The role of renal calbindin-D_9K in the compensation of impaired calbindin-D_28K function (and vice versa) remains an enigma and awaits further investigation.

The maintenance of the Ca²⁺ balance is tightly controlled by PTH and 1,25(OH)₂D₃ through the regulation of TRPV5, which serves the gatekeeper function in the process of active renal Ca²⁺ reabsorption. Calbindin-D_9K is one of the possible candidates that might take over the function of calbindin-D_28K in calbindin-D_28K^–/– mice. Additional physiologic studies on the characterization of mouse strains lacking calbindin-D_9K, calbindin-D_9K/TRPV5, and calbindin-D_9K/calbindin-D_28K/TRPV5, as well as surveys to address physical interactions between calbindin-D_9K and TRPV5, are stirring and complete the dynamic and concerted role of TRPV5 and calbindins in renal Ca²⁺ handling.

	Footnotes

 
Published online ahead of print. Publication date available at www.jasn.org.

See the related article, "Critical Role of the Epithelial Ca²⁺ Channel TRPV5 in Active Ca²⁺ Reabsorption as Revealed by TRPV5/Calbindin-D_28K Knockout Mice," on pages 3020–3027.

	References

Top References

 

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2. Hoenderop JG, Nilius B, Bindels RJ: Calcium absorption across epithelia. Physiol Rev 85 : 373 –422, 2005[Abstract/Free Full Text]
3. Hoenderop JG, van der Kemp AW, Hartog A, van de Graaf SF, van Os CH, Willems PH, Bindels RJ: Molecular identification of the apical Ca2+ channel in 1,25-dihydroxyvitamin D3-responsive epithelia. J Biol Chem 274 : 8375 –8378, 1999[Abstract/Free Full Text]
4. Hoenderop JG, van Leeuwen JP, van der Eerden BC, Kersten FF, van der Kemp AW, Merillat AM, Waarsing JH, Rossier BC, Vallon V, Hummler E, Bindels RJ: Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J Clin Invest 112 : 1906 –1914, 2003[CrossRef][Medline]
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