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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-D28K double-knockout mice and further explored the relationship between TRPV5 and calbindin-D28K, 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-D9K as intracellular ferry of Ca2+, and PMCA1b as the extrusion mechanism.
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Calbindin-D28K, 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-D28k in the process of active renal Ca2+ reabsorption, calbindin-D28K knockout (calbindin-D28K–/–) 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-D28K 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-D28K (TRPV5–/–, calbindin-D28K–/–, and TRPV5–/–/calbindin-D28K–/–) 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-D28K–/– mice displayed prominent Ca2+ abnormalities similar to the TRPV5–/– mice, such as hypercalciuria and increased Ca2+ absorption, whereas calbindin-D28K–/– mice showed a wild-type phenotype. These findings suggest that TRPV5 but not calbindin-D28K may be the critical component in renal active Ca2+ reabsorption.
At the cellular level, a recent study demonstrated that calbindin-D28k 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-D28k 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-D28K diffuses from TRPV5 and facilitates transport of Ca2+ to the basolateral membrane. These data suggest that calbindin-D28k acts as a dynamic Ca2+ buffer, regulating Ca2+ concentration by coordination of TRPV5. Calbindin-D28K and TRPV5 apparently form a functional protein couple essential for renal Ca2+ handling. However, gene-ablation of calbindin-D28k in mice did not affect renal Ca2+ handling. Other unknown Ca2+-binding proteins that substitute the function in calbindin-D28K–/– mice can possibly compensate the calbindin-D28K deficiency. Interestingly, the specific co-expression of calbindin-D9K and calbindin-D28K in mouse DCT cells hints to a comparable function of calbindin-D9K in Ca2+ reabsorption. Recently, Kutuzova and co-workers showed that calbindin-D9K 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-D9K in the compensation of impaired calbindin-D28K 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-D9K is one of the possible candidates that might take over the function of calbindin-D28K in calbindin-D28K–/– mice. Additional physiologic studies on the characterization of mouse strains lacking calbindin-D9K, calbindin-D9K/TRPV5, and calbindin-D9K/calbindin-D28K/TRPV5, as well as surveys to address physical interactions between calbindin-D9K and TRPV5, are stirring and complete the dynamic and concerted role of TRPV5 and calbindins in renal Ca2+ handling.
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Footnotes |
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See the related article, "Critical Role of the Epithelial Ca2+ Channel TRPV5 in Active Ca2+ Reabsorption as Revealed by TRPV5/Calbindin-D28K Knockout Mice," on pages 3020–3027.
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