TRPV6
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TRPV6 is a membrane
Classification
Transient Receptor Potential Vanilloid subfamily member 6 (TRPV6) is an epithelial
Identification
Peng et al identified TRPV6 in 1999 from rat
Gene location, chromosomal location, and phylogeny
The human TRPV6
Species | Human | Rat | Mouse |
Chromosomal location | 7q33-q34 | 4q22 | 6B2 |
Annotated aa length | 725 | 727 | 727 |
In vivo aa lengtha | 765 | 767 | 767 |
RefSeq nucleotide | NM_018646 | NM_053686 | NM_022413 |
RefSeq protein | NP_061116 | NP_446138 | NP_071858 |
aTo be verified in different tissues.
It has been hypothesized that Trpv5 and Trpv6 genes were generated from a single ancestral gene by gene duplication events.[16][19] Phylogenetic analysis has shown that TRPV6 paralogs in mammals, sauropsids, amphibians, and chondrichthyes arose out of independent duplication events in the ancestor of each group.[19] It is speculated that two specialized Ca2+-selective Trpv homologs arose as an adaptation to achieve a greater degree of functional specialization for navigating distinct renal challenges of terrestrial animals.[19]
Two
Tissue distribution
The TRPV6 protein is expressed in
Differences in the TRPV6 expression profile have been reported possibly due to variation in assay-dependent such
In humans, TRPV6 transcripts have been detected in the placenta, pancreas, prostate cancer, and duodenum and the prostate by northern blotting; and in duodenum, jejunum, placenta, pancreas, testis, kidney, brain, and colon by semi-quantitative PCR.[13] In rodents, TRPV6 expression has been validated in the duodenum, cecum, small intestine, colon, placenta, pancreas, prostate, and epididymis by Northern Blotting.[10][17][26] In mouse, TRPV6 transcript abundance measured by RT-PCR is as follows: prostate > stomach, brain > lung > duodenum, cecum, heart, kidney, bone > colon > skeletal muscle > pancreas.[27]
Data from Human Protein Atlas and RNA-Seq based suggest TRPV6 mRNA is low in most tissues except for the placenta, salivary gland, pancreas, and prostate.[24][28] TRPV6 mRNA is expressed in the apical domain of murine osteoclasts of cortical bone.[29][30] Cortical and trabecular osteocytes do not express TRPV6 mRNA whereas osteoblasts show weak expression.[31]
Structure and biophysical properties
Primary and secondary structure
Overall, four subunits of TRPV6 arrange to form a tetrameric channel displaying a four-fold
Tertiary and quaternary structure
The TRPV6 channel protein displays four-fold symmetry and contains two main compartments: a 30 Å-tall transmembrane domain with a central ion channel pore and a ~70 Å-tall and a ~110 Å-wide intracellular skirt enclosing a 50 Å × 50 Å cavity wide cavity underneath the ion channel.[32] The clustering of four TRPV6 subunits forms an aqueous pore exhibiting a fourfold symmetry (Figure 2). A pre-SI helix links the intracellular portion of the protein to the TM domain through a linker domain made up of β-hairpin structure and a helix-turn-helix motif. Helices S1 through S4 form a transmembrane helical bundle or TM domain that is inserted almost perpendicularly to the plane of the plasma membrane.[32]
The pore module elements are made up of S5, S6, and the P-loop in TM domains.[32] The pore module from each TRPV6 polypeptide participates in inter-subunit interactions to form a central ion pore (Figure 1).[32] The pore-forming elements of each TRPV6 subunit also interact with S1-S4 domains of the adjacent polypeptide in a domain-swapped arrangement.[32][33] Intersubunit interactions also occur between S1-S2 extracellular loops and S5-P and S6-P loops of the neighboring TRPV6 subunits.[32] The conserved N-linked glycosylation site on the S1-S2 loop is required for by the Klotho-mediated activation.[34] The intracellular skirt portion of the TRPV6 protein is mainly made up of the ankyrin repeats.[32] The TRP domain is oriented parallel to the membrane and participates in hydrophobic interactions with the TM domain and the hydrophilic interactions in the intracellular skirt. The N-terminal helix, C-terminal hook, and β-sheets (formed by the β-hairpin structure in the linker domain) in the channel participates in intersubunit interactions with the ARDs to provides a framework for holding the elements of the intracellular skirt together.[8][32]
Pore architecture and cation binding sites
The TRPV6 pore has four main elements, namely, the extracellular vestibule, a selectivity filter, a hydrophobic cavity, and a lower gate.[32][35][36] Facing the central lumen of the channel, a four-residue selectivity filter (538TIID541) containing four Aspartate 541 (D541) side chains (one from each protomer) is critical for Ca2+ selectivity and other biophysical properties of the channel.[32][35][36] This filter forms a negatively charged ring that discriminates between ions based on their size and charge. Mutations in the critical pore-forming residue of TRPV6 blocks Ca2+uptake, a strategy has been used to generate TRPV6 loss-of-function models to examine the role of the channel in animal physiology.[35][36] Four different types of cation binding sites are thought to exist in the TRPV6 channel.[32] Site 1 is located in the central pore and shares the same plane that is occupied by the key selective residues D541. Site 2 is thought to be present about 6-8 Å below Site 1 followed by Site 3 which is located in the central pore axis about 6.8 Å below Site 2. Site 2 and 3 are thought to interact with partially-hydrated to equatorially-hydrated Ca2+ ions. Finally, four symmetrical cation binding sites in the extracellular vestibule mediate the recruitment of cations towards the extracellular vestibule of TRPV6 and are referred to as recruitment sites.[32]
Ion permeation
The conductance of TRPV6 for
Channel gating
The conformational changes involved in channel opening are hinged around the residue
Regulation by phosphatidylinositol 4,5-bisphosphate (PIP2) and calmodulin (CaM)
The influx of Ca2+ inside the cell triggers negative feedback mechanisms to suppress TRPV6 activity and prevent Ca2+ overload.[9] TRPV6 channel activity is regulated by the intracellular level of phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) and interactions with Ca2+-Calmodulin (CaM) complex.[9] The depletion of PIP2 or CaM-binding inactivates TRPV6.[40][41][42][43][44] The influx of Ca2+ in TRPV6 expressing cells activates phospholipase C (PLC) which in turn hydrolyzes PIP2. Depletion in PIP2 levels results in a decline in channel activity since most TRP channels require this lipid for activation.[40][43][44] The lipid PIP2 can override Ca2+-CaM-mediated inhibition of TRPV6. Overall, TRPV6 inactivation by calmodulin is orchestrated by a balance of intracellular Ca2+ and PIP2 concentration.[40][41][42][43][44]
Interacting proteins
Among 20+ TRPV6 interactors identified so far, the functional consequences of Ca2+-binding protein Calmodulin (CaM) and Glucuronidase Klotho have been most extensively characterized [36, 37, 41, 42].[34][40][41][45][46] Functional consequences of TRPV6 channel activation are summarized in the table below).[47]
Interactor | Consequence |
BSPRY | N/A |
Calbindin-D28k | N/A |
Calmodulin | Inhibition |
Cyclophilin B | Activation |
FYN | PO4lyation |
I-MFA | N/A |
Klotho | Activation, Glycosylation (Asn-357) |
NHERF4 | Activation |
NIPSNAP1 | Inhibition |
NUMB | Inhibition |
PTEN | N/A |
PTP1B | DePO4lyation
(Tyr-161 and Tyr-162) |
RAB11A | Activation,
Increase in Plasma membrane level |
RGS2 | N/A |
RYR1 | N/A |
S100A10 | Activation,
Increase in Plasma membrane level |
SRC | PO4lyation (Tyr-161, 162) |
TRPC1 | Retains in ER, Inhibition |
TRPML3 | N/A |
TRPV5 | Tetramer formation,
New Channel creation |
Abbreviations
Protein Interactor
BSPRY: B-Box and Spry Domain Containing Protein; FYN: Fyn Kinase Belonging Src Family of Kinases; I-MFA: Myo D Family Inhibitor; NHERF: Na Exchanger Regulatory Factor; NIPSNAP14-Nitrophenylphosphatase Domain and Non-Neuronal SNAP25-Like Protein Homolog 1; Numb: Drosophila mutation that removes most of the sensory neurons in the developing peripheral nervous system; PTP: Protein Tyrosine Phosphatase; Rab11a: Member RAS Oncogene Family; RGS2: Regulator Of G-Protein Signaling 2; RyR1: Ryanodine Receptor 1; TRPC1: Transient receptor potential canonical 1; TRPML3: Transient receptor potential Mucolipin-3.
Physiological functions
The Ca2+-selective channel proteins TRPV6 and TRPV5 cooperate to maintain calcium concentration in specific organs.[22][48] TRPV6 functions as apical Ca2+ entry channels mediating transcellular transport of this ion in the intestine, placenta, and possibly some other exocrine organs. TRPV6 also plays important roles in maternal-fetal calcium transport,[49] keratinocyte differentiation,[50] and Ca2+ homeostasis in the endolymphatic system of the vestibular system,[51][52] and maintenance of male fertility.[53][54]
Ca2+ absorption in intestine
Two routes of Ca2+ absorption are recognized:
Ca2+ reabsorption in the kidney
In contrast to the intestine, where TRPV6 is the gatekeeper of Ca2+ absorption, the transcellular reabsorption of this ion in the kidney occurs through TRPV5. Although TRPV5 is a recognized gatekeeper for transcellular reabsorption of Ca2+ ion in the kidney, TRPV6
Maternal-fetal Ca2+ transport
TRPV6 plays an indispensable role in placental Ca2+ transport.
Epididymal Ca2+ regulation and implications on male fertility
The regulation of calcium concentration in the epididymal lumen is critical for sperm motility.[66] TRPV6-mediated reduction of luminal Ca2+ concentration in the epididymis is critical for male fertility in mice.[53] TRPV6 KO mice or mice expressing loss-of-function version of TRPV6 channel (Trpv6D541A homozygous mice) have a severely impaired fertility.[53] Mice expressing nonfunctional TRPV6 have a 10-fold higher concentration of Ca2+ in the epididymal lumen and Ca2+ uptake in this space is reduced by 7-to-8 folds.[53][54] The increases Ca2+ ion in epididymal lumen concentration leads to significant defects in motility, fertilization capacity, and viability of sperms in TRPV6D541A mice.[53][54] It appears TRPV6 and chloride channel transmembrane manner 16 A (TMEM16A) act cooperatively to reduce the luminal concentration of Ca2+ in the epididymal lumen.[67]
Bone health
Under conditions of sub-optimal dietary Ca2+, normal serum calcium levels in TRPV6 KO mice are maintained at the expense of bone.[68][69] TRPV6 plays an important role in osteoclasts but not in osteoblasts.[68][69] In mice, TRPV6 depletion results in increased osteoclasts differentiation[29] whereas TRPV5 is essential for proper osteoclastic bone resorption.[68]
Keratinocyte differentiation
Keratinocytes differentiation is orchestrated by calcium switch, a process that entails an influx of Ca2+ in keratinocyte which induces broad transcriptional changes necessary for
Role in the inner ear
The proteins TRPV5 and TRPV6 are expressed in several regions of the inner ear as well as in primary cultures of semicircular canal duct (SCCD) epithelium.[51][52] Some studies have indicated that TRPV5 and TRPV6 are needed for lowering the Ca2+ concentration in the lumen of mammalian endolymph, a requirement that is essential for normal hearing and balance.[51][52][71]
Uterine and placental expression of TRPV6 and implications in pregnancy
The
Implications in Human Diseases
Transient Neonatal Hyperparathyroidism
Loss of TRPV6 in murine placenta severely impairs Ca2+ transport across trophoblast and reduces embryo growth, induces bone calcification, and impairs bone development. In humans, the insufficient maternal-fetal transport caused by pathogenic genomic variants of TRPV6 is thought to be a cause for skeletal defects observed in selected case reports of transient neonatal hyperparathyroidism (TNHP) cases. These variants are believed to compromise the plasma membrane localization of the protein.
Chronic Pancreatitis
Recent evidence indicates that naturally occurring TRPV6 loss of function variants predisposes certain
Kidney Stone Formation
The role of TRPV6 in renal stone formation has been suggested through sequencing studies conducted on a
Bone Resorptive Diseases
TRPV6 KO mice exhibit osteoporosis-like symptoms such as reduced
The high degree of similarity between Hereditary Vitamin D–Resistant Rickets (HVDRR) disease symptoms and observed phenotypes in TRPV6 KO mice has led some experts to postulate pathological connections between the disease and TRPV6 dysfunction.[48] TRPV6 plays an important chondroprotective role by regulating multiple aspects of chondrocyte function, such as extracellular matrix secretion, the release of matrix-degrading enzymes, cell proliferation, and apoptosis.[82] Furthermore, TRPV6 knockout mice display multiple osteoarthritis (OA) phenotypes such as cartilage fibrillation, eburnation, and loss of proteoglycans.[82]
Pendred Syndrome
The dysfunction gene
Cancer
The
Expression of TRPV6 is upregulated by estrogen, progesterone, and estradiol in breast cancer cell line
TRPV6 is up-regulated in primary cancer tissues from
Pharmacological Targeting
Several chemical inhibitors are known to inhibit TRPV6. Some compounds that have demonstrated inhibitory activity towards TRPV6 include TH-1177,
Regulation
The regulation of TRPV6 can be examined mainly in the context of its physiological, hormonal, and molecular factors.[22] The hormonal regulation of TRPV6 has been characterized most extensively. In this regard, its regulation by the hormone vitamin D3 and sex hormones has been examined in considerable detail. Rodent studies suggest that the TRPV6 channel is regulated by a wide range of physiological factors such as diet, age, gender, pregnancy, lactation, sex hormones, exercise, age, and gender. Some biological and pharmacological agents known to regulate TRPV6 include glucocorticoids, immunosuppressive drugs, and diuretics.[22]
Vitamin D
Multiple dose-response and time-course experiments in rodents and colon cancer cell lines have conclusively shown TRPV6 mRNA is robustly induced by this vitamin D at extremely low concentrations.
Diet
The level of Ca2+ and vitamin D in the diet are the most important regulators of TRPV6 expression.[104] The expression of TRPV6 is thought to be modulated strongly to fine-tune Ca2+ absorption from the diet, especially under conditions when dietary Ca2+ availability is low.[103][104] In rodents, restricting Ca2+ availability in the diet induces dramatic up-regulation in the duodenal expression of TRPV6.[103][104] Calcium influx from the diet and its subsequent binding to calbindin-D9k could be the rate-limiting step that modulates vitamin D-dependent regulation TRPV6.[108] When dietary Ca2+ is insufficient, normal blood calcium levels in TRPV6 KO mice are maintained at the expense of bone.[68][69] In many rodent lines, genetic variations in TRPV6, calbindin-D9k, PMCA1b mRNA influence intestinal Ca absorption and its impact on bone marrow density.[109]
Pregnancy and lactation
Duodenal expression of TRPV6 transcripts is upregulated in WT and VDR KO mice during pregnancy and lactation.[110] The hormone prolactin upregulates TRPV6 transcription and facilitates an increase in intestinal Ca2+ absorption in lactating and pregnant rats, possibly as an adaptive mechanism for overcoming the loss in bone mineralization content during lactation.[111]
Aging
The intestinal expression of TRPV6 in mice varies dramatically by age and relative tissue location.[112] The duodenal expression of TRPV6 is undetectable at P1 and increases 6-fold as mice age to P14. Similarly, the expression also varies with age in the jejunum, where TRPV6 levels increases from P1 to P14, become weak at 1-month age and becomes undetectable in older mice.[112] The expression of TRPV6 in older rats (12-months) is at least 50% lower in comparison to younger counterparts (2-months old).[104] In both WT and VDR KO mice, the age-associated decline in intestinal absorption of Ca2+ is accompanied by a decline in duodenal expression of TRPV6.[113]
Sex hormones
Sex hormones play an important role in the regulation of TRPV6. In comparison to male mice, female mice exhibit a 2-fold higher increase in duodenal expression of TRPV6 mRNA following vitamin D treatment.[citation needed] Sex hormone-associated differential regulation of TRPV6 across genders is believed to be correlated to differences in relative risk to osteoporosis in older postmenopausal women which have been reported to have lower TRPV6 and VDR expression in comparison to males.[81]
Estrogen treatment upregulates TRPV6 transcripts by 8-fold in VDR KO mice and by 4-fold in
Glucocorticoids
Subcutaneous administration of glucocorticoids dexamethasone induces both renal and intestinal expression of TRPV6 in mice within 24 hours of whereas oral application of prednisolone reduction in TRPV6 which is also accompanied by reduced Ca2+ absorption in duodenum.[117][118] Intestinal regulation of TRPV6 in response to glucocorticoids appears to be VDR-dependent.[117][118] The enzyme serum and glucocorticoid-regulated kinase 1 (SKG1) regulates TRPV6 expression by enhancing phosphatidylinositol-3-phosphate-5-kinase PIKfyve (PIP5K3).[119] This kinase is critical for the generation of secondary messenger PIP2, a known lipid activator of TRPV6.[119]
- TRPV
- TRPV5
- calcium channels
- calcium absorption
- transcellular pathway
- gating mechanism
- calmodulin
- maternal-fetal transport
- transient neonatal hyperparathyroidism
- chronic pancreatitis
- kidney stones
- cancer
Notes
Wikidata Q110874871 . |
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Further reading
- Heiner I, Eisfeld J, Lückhoff A (2004). "Role and regulation of TRP channels in neutrophil granulocytes". Cell Calcium. 33 (5–6): 533–40. PMID 12765698.
- Clapham DE, Julius D, Montell C, Schultz G (December 2005). "International Union of Pharmacology. XLIX. Nomenclature and structure-function relationships of transient receptor potential channels". Pharmacological Reviews. 57 (4): 427–50. S2CID 17936350.
- Wissenbach U, Niemeyer BA (2007). "TRPV6". Transient Receptor Potential (TRP) Channels. Handbook of Experimental Pharmacology. Vol. 179. pp. 221–34. PMID 17217060.
- Schoeber JP, Hoenderop JG, Bindels RJ (February 2007). "Concerted action of associated proteins in the regulation of TRPV5 and TRPV6". Biochemical Society Transactions. 35 (Pt 1): 115–9. PMID 17233615.
External links
- TRPV+Cation+Channels at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- TRPV6+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)