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REVIEW

Calciotropic and Magnesiotropic TRP Channels

Joost G. J. Hoenderop and René J. M. Bindels

Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands r.bindels{at}ncmls.ru.nl

	Abstract

 
Significant progress has been made into our understanding of the molecular mechanisms responsible for Ca²⁺ and Mg²⁺ homeostasis. Members of the transient receptor potential channel (TRP) superfamily proved essential to the maintenance of divalent cation levels by regulating their absorption from renal and intestinal lumina. This review highlights the molecular and functional aspects of these new calciotropic and magnesiotropic TRPs in health and disease.

	Physiology of Ca2+ and Mg2+ Homeostasis

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 
Ca²⁺ and Mg²⁺ are of central importance for multiple essential physiological functions, not the least of which include muscle contraction, neuronal excitability, bone formation, and enzymatic activity (25). Consequently, their concentration throughout the body is tightly regulated by an efficient feedback control system through the concerted action of kidney, intestine, and bone. Specifically, they are absorbed by the gastrointestinal tract and filtered and reabsorbed in the kidney, whereas the bone acts as a dynamic storage compartment, releasing divalent cations into blood when needed, i.e., on deprivation. Ca²⁺ and Mg²⁺ (re)absorption by these organs is mediated by paracellular as well as transcellular transport processes. The paracellular component of epithelial Ca²⁺ and Mg²⁺ transport is passive, directly connecting the luminal compartment with the blood compartment. By contrast, transcellular transport is active, involving the passage of two plasma membrane barriers (FIGURE 1). The latter is specifically regulated by the combined action of various calciotropic and magnesiotropic hormones.

View larger version (83K): [in this window] [in a new window]   FIGURE 1. Transcellular Ca2+ and Mg2+ transport across renal and intestinal epithelia A: luminal Ca2+ influx is mediated by TRPV5 in the renal distal convoluted and connecting tubules and TRPV6 in the duodenum. Subsequently, Ca2+ is transported across the cell to the basolateral membrane by Ca2+-binding proteins calbindin-D28K (kidney) and calbindin-D9K (intestine). Extrusion into the blood takes place via the plasma membrane Ca2+-ATPase (PMCA1b) in the intestine and Na/Ca2+ exchanger (NCX1) and PMCA1b in the kidney. B: luminal Mg2+ influx is mediated by TRPM6 in the renal distal convoluted tubules and the intestine. Subsequently, Mg2+ is transported across the cell to the basolateral membrane and extruded into the blood. The molecular identity of the latter players remains unknown at present. In this way, there is net Ca2+ and Mg2+ (re)absorption from the luminal space to the extracellular compartment.

There is ample evidence that cytosolic diffusion of Ca²⁺ ions inside of epithelial cells is mediated by specific Ca²⁺-binding proteins, known as calbindins. These proteins greatly enhance the diffusion rate of Ca²⁺. Two separate proteins have been described to date: calbindin-D_28K, which is primarily present in renal epithelia, and calbindin-D_9K, which is predominantly located in the intestine (20). Specific Mg²⁺-binding proteins have not been identified thus far, although the calbindins have been shown to bind Mg²⁺ as well. The physiological relevance of this is uncertain since the cytosolic Mg²⁺ concentration is typically in the submillimolar range, questioning the need for specific binding proteins to enhance the cytosolic diffusion rate of Mg²⁺ (1). Once at the basolateral membrane, Ca²⁺ is extruded into the blood by the Na⁺/Ca²⁺ exchanger (NCX1) and the plasma membrane Ca²⁺-ATPase (PMCA1b). Both these proteins are exclusively localized to the basolateral membrane of epithelial cells (FIGURE 1) (25). The characteristics of potential Mg²⁺ extrusion proteins are lacking to date, and new initiatives should be focussed in this direction. Regulation of active transcellular absorption occurs predominantly at the luminal membrane. The tightly regulated, apically expressed Ca²⁺ and Mg²⁺ channels have been identified in the last decade through expressional cloning and gene linkage analysis, respectively (26, 55, 61, 82). The identified channels belong to the superfamily of the transient receptor potential channels (TRPs) and are the topic of this review.

	Introduction to Calciotropic and Magnesiotropic TRP Channels

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 
Mammalian TRP channels are cation-permeable channels that have been subgrouped into six categories on the basis of sequence homology (i.e., TRPC, TRPV, TRPM, TRPA, TRPP, and TRPML) (7, 49). They are among the largest family of ion channels known, with representative members in a diverse range of species from yeast to humans. TRP channels are involved in a variety of physiological processes ranging from sensory functions to smooth muscle proliferation, endothelial permeability, gender-specific behavior, and epithelial divalent ion transport (25, 49, 64, 77). It is generally postulated that TRP channels span the membrane six times, have a hydrophobic pore loop between transmembrane regions 5 and 6, and contain large intracellular amino- and carboxyl-termini (FIGURE 2, A AND B). TRPs typically assemble into (hetero)tetramers to form a functional cationic channel, which permits the influx of Na⁺, Ca ²⁺, or Mg²⁺ ions. The stoichiometry and composition of the heterotetramer is determined by the ability of homologous members to interact with each other (21).

View larger version (76K): [in this window] [in a new window]   FIGURE 2. Characteristics of calciotropic and magnesiotropic TRP channels The proposed topology of the TRP channel includes six transmembrane (TM)-spanning domains and a pore-forming unit between TM5 and TM6. A: proposed structure of calciotropic TRPV5 and TRPV6 channels, including regulatory domains. Ankyrin repeats present in the amino-terminus of TRPV5 and TRPV6 are depicted with ANK. TRPV5 contains two protein kinase C (indicated by C) phosphorylation sites that are important for tissue-kallikrein-stimulated channel activity. In addition, the channel is N-glycosylated at position N358 (numbering of rabbit species) between TM1 en TM2. B:proposed structure of the magnesiotropic TRPM6 channel. TRPM6 is a protein that is both an ion channel and a kinase. The fused kinase domain at the carboxyl-terminus belongs to the -kinase. The kinase is capable of phosphorylating itself and other potential substrates. The kinase activity is dependent on the intracellular ATP concentration that can bind the kinase domain. C:channel regulation can take place at various levels in the epithelial cell. First, the abundance of TRP channels is regulated by transcriptional and translational processes in the epithelial cell (1). The cell surface expression of TRPs is controlled in a dynamic way by insertion and retrieval pathways adjusting the requested functional activity at the plasma membrane (2). Finally, these TRP channels are gated at the cell surface by intracellular Ca2+ and Mg2+, providing a negative feedback regulation (3).

	The Calciotropic TRP Channels

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

TRPV5 is predominantly expressed in the distal convoluted (DCT) and connecting (CNT) tubule of the kidney. These nephron segments are known to be involved in transcellular Ca²⁺ reabsorption. Here, the channel co-localizes with the previously described Ca²⁺ transporters, calbindin-D_28K, NCX1, and PMCA1b. TRPV5 is also expressed, albeit at a lower level, in osteoclasts where it contributes to Ca²⁺ resorption (Table 1) (76). In contrast to TRPV5, TRPV6, is more ubiquitously expressed with significant expression levels in small intestine, mammary gland, and also prostate (52). Intestinal TRPV6 expression is mainly restricted to proximal duodenum where it is co-expressed with calbindin-D_9K and PMCA1b (FIGURE 1) (25, 53).

	Lessons from TRPV5 and TRPV6 Knockout Mice Models

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

A disturbed Ca²⁺ homeostasis was also observed in mice lacking TRPV6 (TRPV6^–/–). They display defective intestinal Ca²⁺ absorption, low bone mineral density, decreased weight gain, and reduced fertility (2). Furthermore, TRPV6^–/– mice display increased urinary Ca²⁺ excretion, although at low levels this Ca²⁺ channel is also expressed in the kidney, suggesting that it plays a role in renal Ca²⁺ handling (2). Finally, the skin of TRPV6^–/– mice has fewer and thinner layers of stratum corneum, and ~20% percent of these animals develop alopecia and dermatitis (2). The applied TRPV6 knockout targeting strategy affected, in addition to the TRPV6 gene, also the closely adjacent EphB6 gene that might have contributed to the observed phenotype. Taken together, TRPV6^–/– mice exhibit an array of abnormalities in multiple organs, reflecting an important role in Ca²⁺ homeostasis and beyond.

	Pathophysiology of TRPV5 and TRPV6

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 
Numerous clinical disorders and side effects from commonly prescribed medication cause electrolyte disturbances, resulting in the dysregulation of whole body Ca²⁺ balance. TRPV5 and TRPV6 have been suggested to contribute to the pathogenesis of altered Ca²⁺ homeostasis observed in both kidney diseases and from drug treatment therapies (29, 64). Because the abnormalities observed in TRPV5^–/– and TRPV6^–/– mice are also reported in patients with idiopathic hypercalciuria and/or Ca²⁺ malabsorption, TRP channel dysfunction may contribute to the pathogenesis of such disorders in humans. Despite several efforts, mutations in these channels have, however, not yet been identified (43). Commonly prescribed medications, including diuretics, immunosuppressant agents, and vitamin D analogs, may cause TRP channel-associated mineral (dys)regulation. Immunosuppressant drugs, such as tacrolimus and the glucocorticoids dexamethasone and prednisolone, are prescribed for a wide array of renal diseases and themselves affect the expression of TRPV5 and TRPV6 (Table 2). In addition, acid-base status affects the handling of Ca²⁺ (47). Chronic metabolic acidosis, a complication of renal failure, distal renal tubular acidosis, and chronic diarrhea are associated with increased renal Ca²⁺ excretion. An acid load in mice is accompanied by decreased renal TRPV5 expression, explaining the calciuresis observed under these conditions. A detailed overview of the (dys)regulation of TRPV5 and TRPV6 under various circumstances is summarized in Table 2.

	The Magnesiotropic TRP Channel

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

	Pathophysiology of TRPM6

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 
HSH is an autosomal recessive disorder that manifests in early infancy with generalized convulsions and symptoms of increased neuromuscular excitability, including muscle spasms and tetany (33). The pathophysiology of HSH is largely unknown, but physiological studies indicate a primary defect in intestinal Mg²⁺ transport. Previously, a gene locus for HSH was mapped to chromosome 9q22, the locus of TRPM6. Subsequently Konrad et al. and Sheffield et al. independently identified truncation and missense mutations in TRPM6 as the likely causative genetic defect in HSH (60, 61, 82). Consistent with their observations, the identified mutations in TRPM6 abolish channel activity (6, 81). Localization of TRPM6 to the DCT confirmed the earlier hypothesis of Cole and Quamme that renal Mg²⁺ wasting contributes significantly to the pathogenesis of HSH (8). This is further supported by intravenous Mg²⁺-loading tests in HSH patients, who exhibit a considerable renal Mg²⁺ leak during hypomagnesemia. As already discussed for disturbances in Ca²⁺ homeostasis, commonly prescribed medication used to treat renal and intestinal diseases affect whole body Mg²⁺ status through an alteration in the expression of TRPM6. An overview of our current view with respect to this regulation is summarized in Table 2.

	Controlling TRP Channel Activation

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 
Calciotropic and magnesiotropic TRP channels are integral membrane proteins that mediate the apical influx of Ca²⁺ and Mg²⁺. When open, these TRP channels, provide a diffusion pathway across the apical membrane, permitting the reabsorption of these solutes. Typically, they have a high throughput, allowing the flux of millions of ions per second and therefore require tight regulatory control of the channel’s open state. This positions the calciotropic and magnesiumtropic TRPs to be ideal targets for control of divalent cation reabsorption. Minute-to-minute whole body Ca²⁺ and Mg²⁺ status is adjusted by the regulation of these channels. The whole cell patch-clamp configuration enables the measurement of the current present at the plasma membrane. These currents (I) correspond to the formula I = i · N · P, where i represents the single-channel current (in pA), N is the number of ion channels in the plasma membrane, and P is the open probability of the channels. Trafficking of the channel into and out of the apical plasma membrane alters the number of surface-exposed channels (FIGURE 2C). Further fine tuning occurs through channel gating once inserted into the plasma membrane. The most basic aspect of channel regulation takes place by feedback control through the intracellular concentration Ca²⁺ and Mg²⁺ itself. Once the Ca²⁺ concentration in close vicinity to the channel pore of TRPV5 and TRPV6 reaches a threshold concentration, it acts as a negative feedback regulator, inactivating the channel at the cell surface (50, 78) (FIGURE 2C). Similar observations were made for intracellular Mg²⁺ with respect to TRPM6 channel activity. These TRPs rapidly inactivate during hyperpolarizing voltage steps in a Ca²⁺- or Mg²⁺-dependent fashion, respectively (78). In addition, TRP channels are regulated by a wide variety of physical and chemical factors. Recently, several members of the TRP channel family were reported to be regulated by phosphatidylinositol 4,5-bisphosphate (PIP₂), including TRPV and TRPM channels (57). Future studies will hopefully address the physiological relevance of PIP₂ in controlling calciotropic and magnesiotropic TRP channel activity.

Extracellular protons have a profound and diverse effect on TRP channel activity. Protons inhibit the calciotropic TRP channels by binding to glutamate-522 (E⁵²²) within the extracellular domain of the channel (84). E⁵²² has been postulated to be an extracellular "pH sensor," and its titration by extracellular protons reduces TRPV5 channel activity via conformational changes of the pore helix (84). In addition, the extra-cellular pH determines the cell surface expression of these TRP channels. An alkaline environment rapidly increases the number of channels at the plasma membrane, whereas an acidic milieu produces the opposite effect (36). Conversely, the magnesiotropic TRPs are stimulated by extracellular protons. Here, the small inward current of TRPM6 and TRPM7 is significantly enhanced by a decrease in extracellular pH. The ability of protons to potentiate inward currents in TRPM6 is lost in the E¹⁰²⁴Q mutant, suggesting that this amino acid is critical to both Mg²⁺ permeability and its pH sensitivity (39).

	Interacting Proteins

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 
Several interesting regulatory proteins of these TRPs have now been described in detail (for an overview, see Table 2 and Ref. 71). Most of these regulators alter channel trafficking (FIGURE 2C). The first such interacting protein identified is the S100A10 protein. It forms a heterotetrameric complex with annexin 2 and associates specifically with the conserved sequence (VATTV) located in the carboxyl-terminal tail of TRPV5 and also TRPV6 (73). This associated S100 protein complex facilitates the movement of the calciotropic TRPs toward the luminal plasma membrane. Subsequently, other interacting protein candidates have been pulled out of yeast-two hybrid analysis utilizing kidney cDNA libraries and confirmed by pull-down assays using renal cell lysates. NHERF2, rab11a, and S100A10 regulate the transfer of TRPV5 and/or TRPV6 toward the plasma membrane, whereas the EF-hand-containing proteins calmodulin, calbindin-D_28K, and 80K-H are thought to be regulatory factors of channel activity at the plasma membrane. In addition, other interacting partners such as FKBP52, NHERF2 and 4, and BSPRY have a significant impact on channel activity; however, their molecular mechanism of action is not yet known (Table 2). Future experiments should address in detail the cell biological aspects of vesicular TRPV5/6 transport and the regulation of channel gating kinetics by these and other associated proteins. To date, there is no information with respect to regulatory proteins for the magnesiotropic channel TRPM6.

"Extracellular protons have a profound and diverse effect on TRP channel activity."

	Novel Calciotropic and Magnesiotropic Hormones

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 
Our understanding of the calciotropic and magnesiotropic hormones has evolved over the last years (Table 2). Ours and other laboratories have demonstrated stimulatory effects of the classical calciotropic hormones, vitamin D and parathyroid hormone (PTH), on transepithelial Ca²⁺ transport. In vitro and in vivo studies show that 1,25-dihydroxivitamin D₃ [1,25(OH)₂D₃] stimulates Ca²⁺ (re)absorption from the small intestine and renal DCT and CNT cells. The mechanism of action is via an upregulation of mRNAs encoding TRPV6, TRPV5, the calbindins, and NCX1, which translates into increased Ca²⁺ (re)absorption. More recently, new hormones have been identified that regulate the Ca²⁺ balance, including the female sex hormone estrogen (67). Estrogen deficiency causes a negative Ca²⁺ balance and bone loss in post-menopausal women. Estrogen increases renal expression of TRPV5 in a 1,25(OH)₂D₃-independent manner (67). This was confirmed in ovariectomized vitamin D-deficient mice where 17β-estradiol replacement therapy elevated renal TRPV5 expression, leading to the normalization of serum Ca²⁺ levels. By altering TRPV5 expression, the rate-limiting step in transcellular Ca²⁺ transport, estrogen might positively regulate Ca²⁺ reabsorption and homeostasis (see Table 1 for complete overview).

Recently, the family of the calciotropic hormones has been expanded to include a new member, the anti-aging hormone klotho. Klotho is a type I trans-membrane protein with β-glucuronidase activity. This activity is contained in the extracellular domain that can be secreted into the blood, urine, and cerebrospinal fluid. Klotho-deficient mice suffer from premature aging and display altered Ca²⁺ homeostasis resulting in osteopenia (34). The nephrology community has shown significant interest in klotho due to its predominant renal expression, its co-localization with TRPV5 in the DCT, and its interaction with fibroblast growth factor-23 to regulate phosphate homeostasis (66). Klotho modifies the N-glycan of TRPV5 via its β-glucuronidase activity, resulting in increased channel abundance at the plasma membrane (Table 2) (5). This is the first example of a calciotropic hormone operating from the urinary compartment to stimulate Ca²⁺ channel activity. Subsequently, Imura and coworkers further strengthen the role of klotho in Ca²⁺ homeostasis. They described an association of klotho with the ubiquitous Na⁺-K⁺-ATPase that augments the cell surface expression of this pump. This would increase the driving force for Ca²⁺ efflux, as Ca²⁺ is exchanged for Na⁺ down an increased concentration gradient, by the basolateral NCX1 primarily present in the DCT cell (31). Overall the combined action of klotho on the DCT enhances here the Ca²⁺ reabsorption.

Another hormone affecting Ca²⁺ balance is tissue kallikrein. This is the main mammalian kinin-forming enzyme that is produced by the kidney, where it co-localizes with TRPV5 (16). Other than being a major protein synthesized in the distal part of the nephron, this hormone is also abundantly secreted into tubular fluid. Tissue kallikrein displays serine protease activity that converts kininogen to kinin; this protein then acts by stimulating kinin receptors such as the bradykinin receptor type 2. The first observation that tissue kallikrein plays a role in Ca²⁺ homeostasis came from tissue kallikrein knockout mice, which display significant hypercalciuria (56). These findings suggest that tissue kallikrein deficiency disturbs renal tubular Ca²⁺ reabsorption. Experimental evidence indicates that tissue kallikrein directly activates TRPV5 by protein kinase C-mediated phosphorylation (FIGURE 2A). In a similar fashion to klotho, this factor enhances channel surface expression and consequently increased channel activity. Unraveling the molecular mechanisms of TRPV5 channel regulation by klotho, tissue kallikrein, and other extracellular factors has demonstrated the existence of novel regulatory mechanisms for active trancellular Ca²⁺ reabsorption that act from the pro-urine.

In the past, several hormones have been postulated to be significant players in the maintenance of Mg²⁺ homeostasis; however, convincing data of their effect on epithelial Mg²⁺ transport or TRPM6 activity is lacking. It has been shown that 17β-estradiol but not 1,25(OH)₂D₃ or parathyroid hormone regulates TRPM6 renal mRNA levels (18). TRPM6 expression in kidneys of ovariectomized rats is significantly reduced, whereas 17β-estradiol treatment normalizes TRPM6 mRNA levels. Groenestege et al. recently identified epidermal growth factor (EGF) as a new magnesiotropic hormone regulating renal handling of Mg²⁺ by unraveling the mechanism responsible for a rare inherited Mg²⁺ wasting disorder in a consanguineous kindred (19). Two affected sisters in a large Dutch family displayed increased urinary Mg²⁺ excretion, despite having low serum Mg²⁺ levels (0.53–0.66 mM), consistent with a disturbance in tubular reabsorption of Mg²⁺. The causative mutation was identified to be the pro-EGF gene, which was shown to be a novel magnesiotropic hormone (19). Pro-EGF exists as a membrane-bound molecule that is proteolytically cleaved to generate a 53-amino acid peptide hormone, EGF. The processed EGF is detectable in serum, cerebrospinal fluid, and urine, indicating that mature EGF might be important for maintaining Mg²⁺ balance. In kidney, pro-EGF is primarily expressed in the DCT where it is secreted from the apical and baso-lateral membranes (19). The EGFR is localized baso-laterally in most epithelial cells and can be found throughout the entire nephron with a predominant localization to the basolateral membrane of the DCT (14, 59). Groenestege et al. demonstrated that EGF stimulates TRPM6 through activation of the EGFR in the DCT cell. The mutation observed is a substitution of a highly conserved proline in pro-EGF that prevents the normal processing and secretion of EGF. As a consequence, the EGFR cannot be activated, and TRPM6-mediated Mg²⁺ influx is diminished, causing the renal Mg²⁺ wasting observed in isolated autosomal recessive renal hypomagnesemia (19).

These findings contribute to our increasing understanding of the kidney’s role in endocrinology as a production site of hormones. The calciotropic hormone 1,25(OH)₂D₃ is formed in the proximal tubule, whereas klotho and tissue kallikrein are produced in the DCT and the CNT and then secreted into the urine. Finally, EGF is synthesized in the DCT and released into the urine and blood stream to act as an autocrine/paracrine magnesiotropic hormone in the control of Mg²⁺ reabsorption.

	Further Questions

Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 
It is apparent that the calciotropic and magnesiotropic TRP channel members are central to transepithelial Ca²⁺ and Mg²⁺ transport, thereby regulating whole body Ca²⁺ and Mg²⁺ balance. Although several studies have provided new information with regard to the regulation of these TRPs, the molecular mechanisms responsible for their trafficking and activation within epithelial cells is largely unknown. The kinetics of channel internalization and their fate once internalized is poorly understood. Other than TRPM6, the epithelial Mg²⁺ transporters that facilitate transcellular Mg²⁺ reabsorption remain to be identified. Channel interacting proteins that affect the activity of this magnesiotropic channel need to be elucidated. In addition, the role of the -kinase domain in the carboxy terminus of TRPM6 is not well understood. Furthermore, other TRP channels could contribute to epithelial Ca²⁺ and Mg²⁺ transport like the nonselective cation channel TRPV4 that is highly expressed in kidney (65). Future studies should address these questions. This will provide a better understanding of the function and regulation of these calciotropic and magnesiotropic TRPs. In turn, this will confer greater insight into the maintenance of Ca²⁺ and Mg²⁺ homeostasis.

	Acknowledgments

 
We thank Dr. T. Alexander for critical reading of this manuscript.

This work was financially supported in part by grants from the Dutch Kidney Foundation (C03.6017 and C06.2170), Human Frontiers Science Program (RGP32/2004), the Netherlands Organization for Scientific Research (Zon-Mw 016.006.001, Zon-MW 9120.6110, NWO-ALW 814.02.001, TOPCW 05.B.012), and the Dutch Stomach-Intestine-Liver Foundation (MWO 03-19). J. Hoenderop is supported by an European Young Investigator Award.

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Top Physiology of Ca2+ and... Introduction to Calciotropic and... The Calciotropic TRP Channels Lessons from TRPV5 and... Pathophysiology of TRPV5 and... The Magnesiotropic TRP Channel Pathophysiology of TRPM6 Controlling TRP Channel... Interacting Proteins Novel Calciotropic and... Further Questions References

 

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