Адам TRPV6 гені: кальций тасымалы мен денсаулықтағы ролі

Protein coding gene in the species Homo sapiens

TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine.

Transient Receptor Potential Vanilloid subfamily member 6 (TRPV6) is an epithelial Ca2+ channel that belongs to the transient receptor potential family (TRP) of proteins. The TRP family is a group of channel proteins critical for ionic homeostasis and the perception of various physical and chemical stimuli. TRP channels can detect temperature, osmotic pressure, olfaction, taste, and mechanical forces. The human genome encodes for 28 TRP channels, which include six TRPV channels. TRPV5 and TRPV6 are involved in Ca2+ transport, whereas TRPV1 through TRPV3 are heat sensors with different temperature threshold for activation, and TRPV4 is involved in sensing osmolarity. Genetic defects in TRPV6 gene are linked to transient neonatal hyperparathyroidism and early onset chronic pancreatitis. Dysregulation of TRPV6 is also involved in hypercalciuria, kidney stone formation, bone disorders, defects in keratinocyte differentiation, skeletal deformities, osteoarthritis, male sterility, Pendred syndrome, and certain sub types of Cancer. TRPV6 was also called calcium transport protein 1 (CaT1) initially although the names epithelial calcium channel 2 (ECaC2) and CaT1 like (CaT L) were also used in early studies to describe the channel.

The human TRPV6 gene is located on chromosomal locus 7q33 34 close to its homolog TRPV5 on 7q35. The TRPV6 gene in human encodes for 2906 bp long mRNA. TRPV6 protein bears a 40 a. a long N terminal extension in placenta and in some physiological settings in comparison to the annotated version of the protein used in biological studies. 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. The polymorphisms give rise to an “ancestral variant” and a “derived variant” that differ in five bases and three amino acids. The frequency of the ancestral TRPV6 allele varies across different population groups.

The TRPV6 protein is expressed in epithelial tissues such as the intestine, kidney, placenta, epididymis, and exocrine glands such as pancreas, prostate and salivary, sweat, and mammary glands. TRPV6 protein expression in humans has been demonstrated in the esophagus, stomach, small intestine, colon, pancreas, mammary glands, ovary, thyroid, and prostate by immunohistochemistry approaches. TRPV6 expression profile is also influenced by age, gender, Ca2+ and vitamin D3 levels in food, hormonal status, location within the tissue, cellular location, reproductive status, and weaning status (see Section Regulation). 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. 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. 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. TRPV6 mRNA is expressed in the apical domain of murine osteoclasts of cortical bone. Cortical and trabecular osteocytes do not express TRPV6 mRNA whereas osteoblasts show weak expression.

The Ca2+ selective channel proteins TRPV6 and TRPV5 cooperate to maintain calcium concentration in specific organs. 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, keratinocyte differentiation, and Ca2+ homeostasis in the endolymphatic system of the vestibular system, and maintenance of male fertility.

Two routes of Ca2+ absorption are recognized: paracellular transport and transcellular transport (see Figure 4). A high Ca2+ diet favors paracellular transport of the ion across the length of the intestine allowing them to pass between the intercellular tight junctions that connect epithelial cells. In contrast under conditions when [Ca2+] in the lumen of the intestine is lower in comparison to its concentration in the plasma (e. g. during low dietary Ca2+), the transcellular pathway is required for adequate Ca2+ absorption. Three important steps in transcellular Ca2+ transport are recognized: cellular entry of Ca2+ ion on the apical side via TRPV6 (Step 1), the binding of Ca2+ ion with calbindin D9k (Step 2), and exit of Ca2+ from the basolateral side via the plasma membrane Ca2+ ATPase (PMCA1b). TRPV6 is known to co localize with TRPV5 Calbindin D28K in apical domains of distal convoluted tubules and connecting tubules [20]. TRPV5 KO mice compensate for Ca2+ loss by increasing TRPV6 expression in the duodenum.

TRPV6 plays an indispensable role in placental Ca2+ transport. This process is very important since defects in placental transport of calcium can be precursors for Ca2+ deficiency syndromes and intrauterine growth restrictions. The expression of TRPV6 increases 14 fold during the last 4 days of the murine gestational period and coincides with the peak phase of fetal bone mineralization. Indeed, TRPV6 expression is ~1000 fold higher in comparison to TRPV5. In the placenta, TRPV6 is expressed in trophoblasts and syncytiotrophoblasts.

The regulation of calcium concentration in the epididymal lumen is critical for sperm motility. TRPV6 mediated reduction of luminal Ca2+ concentration in the epididymis is critical for male fertility in mice.

Under conditions of sub optimal dietary Ca2+, normal serum calcium levels in TRPV6 KO mice are maintained at the expense of bone. TRPV6 plays an important role in osteoclasts but not in osteoblasts. TRPV6 KO mice display thinner layers of stratum corneum and 20% of the mice also show alopecia and dermatitis. The expression of TRPV6 in the uterus is thought to be hormonally regulated by 17β estradiol and progesterone in rodents. In rodents, TRPV6 mRNA is expressed in the labyrinth and spongy zone as well as placenta unattached areas of the uterus. The stage of pregnancy is an important regulator of TRPV6 expression. The downregulation of TRPV5/6 expression and a resulting decline in Ca2+ transport is thought to change the proliferative profile of human trophoblasts; a process which in turn is linked to the development of pre eclampsia.

Recent evidence indicates that naturally occurring TRPV6 loss of function variants predisposes certain demographics to chronic pancreatitis (CP) by dysregulating calcium homeostasis in the pancreatic cells. Sequencing studies among chronic pancreatitis patients revealed the presence of 33 missense and 2 nonsense variants predisposed Japanese, German, and French patients to a higher risk of CP. The studies revealed that the frequency of TRPV6 gain of function haplotype is significantly higher in Ca2+ stone formers (nephrolithiasis) in comparison to non formers. The observed hypercalciuria phenotypes from animal studies and studies on TRPV6 single nucleotide polymorphisms (SNPs) suggest that TRPV6 haplotype could be an important risk factor for absorptive and renal hypercalciuria (kidney stones due to impaired intestinal absorption and renal re absorption respectively). The lower incidence of kidney stone diseases in African Americans and a relatively higher prevalence of ancestral haplotype suggest theory according to which this haplotype endows an advantage of increased Ca2+ reabsorption in this demographic and reduces the incidence of kidney stones. The C terminal portion of Soricidin is a drug that inhibits Ca2+ uptake activity by binding to TRPV6. Preclinical studies of this drug have shown great promise in the treatment of bone resorptive diseases. Furthermore, TRPV6 knockout mice display multiple osteoarthritis (OA) phenotypes such as cartilage fibrillation, eburnation, and loss of proteoglycans. The disease is caused by mutations in which compromise the function of the encoded protein pendrin an anion Cl−/HCO3 − exchanger expressed in the inner ear. non small cell lung cancer, and renal cancer. TRPV6 is considered to be an oncochannel that is hypothesized to mediate cancer progression by triggering Ca2+ entry induced aberrations in molecular drivers regulating processes such as cell cycle, apoptosis, and migration; thereby conferring proliferative and survival advantages to cancer cells. Overexpression of TRPV6 correlates strongly with pathological stage, tumor grade, extra prostatic invasion, lymph node metastasis, and resistance to androgen targeted therapies in prostate cancer. The expression TRPV6 has been touted as a prognostic marker for advanced prostate cancer since its expression is strongly dependent on the grade of the tumor. TRPV6 expression has been reported multiple breast cancer cell lines and prostate cancer cell lines. The prostate cancer cell lines PC 3 and LnCAP overexpress TRPV6 relative to benign epithelial cells PrEC and BPH 1. The overexpression of TRPV6 is associated with early stage colon cancer and its silencing in colon cancer induces apoptosis and inhibits cancer cell proliferation. In terms of mechanism, mutations within the calmodulin binding domains of TRPV6 channels confers invasive properties to colon adenocarcinoma cells. The proteins p38α and GADD45α are believed to upregulate TRPV6 expression signaling in SW480 colon cancer cells by enhancing vitamin D signaling. TRPV6 has been reported to amplify Insulin like growth factors (IGF) induced PI3K PDK1 Akt signaling in human colon cancer and promote colon cancer. TRPV6 is up regulated in primary cancer tissues from pancreatic cancer patients and promotes the proliferation of pancreatic neuroendocrine tumors NFAT dependent mechanisms. Silencing of TRPV6 induces apoptosis and cell cycle arrest in pancreatic cancer cells and inhibits their invasion, proliferation, and migration. Forced expression of TRPV6 in gastric cancer cells increases their sensitivity to capsaicin induced apoptosis whereas the siRNA mediated silencing of the channel suppresses this sensitivity. TRPV6 downregulation in esophageal carcinoma has been suggested to be a prognostic marker of disease specific survival in patients suffering from esophageal cancer. Low TRPV5 and TRPV6 co expression have suggested as predictive markers for poor recurrence free survival in non small cell lung cancer. At least five vitamin D response elements (VDREs) at positions −1.2, −2.1, −3.5, −4.3, and −5.5 kb relative to transcriptional start site (TSS) have been identified on TRPV6 transcripts. Among these five sites, VDREs at positions −1.2, −2.1, and −4.3 kb are significantly more responsive to 1,25 (OH)2D3 in comparison to VDREs located at −3.5 and −5.5 kb which do not appear to contribute substantially to vitamin D mediated transcriptional regulation in the intestine. Important steps in vitamin D mediated transcriptional regulation include 1) binding of vitamin D on its cognate vitamin D receptor (VDR), 2) the translocation of vitamin D receptor (VDR) retinoid X receptor heterodimer complex in the nucleus, 3) binding VDR RXR complex on the TRPV6 gene promoter, 4) recruitment of steroid receptor coactivator 1 and RNA polymerase II on the promoter, and 5) transcriptional activation mediated through histone H4 acetylation events.

The level of Ca2+ and vitamin D in the diet are the most important regulators of TRPV6 expression. When dietary Ca2+ is insufficient, normal blood calcium levels in TRPV6 KO mice are maintained at the expense of bone.

Duodenal expression of TRPV6 transcripts is upregulated in WT and VDR KO mice during pregnancy and lactation. 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.

The intestinal expression of TRPV6 in mice varies dramatically by age and relative tissue location. 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.

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. 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. Anti progesterone agent RU486 and anti estrogen agent ICI 182,780 suppress TRPV6 expression in rodents by their respective antagonist action on progesterone and estrogen receptors. Estrogen, progesterone, and dexamethasone are known to upregulate TRPV6 expression in the cerebral cortex and hypothalamus of mice suggesting a potential involvement of TRPV6 in calcium absorption in the brain.