TRPV6 is a membrane calcium (Ca2+) channel protein which is particularly involved in the first step in Ca2+absorption in the intestine.
Classification 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. The high Ca2+-selectivity of TRPV5 and TRPV6 makes these channels distinct from the other four TRPV channels (TRPV1-TRPV4). 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.
Identification Peng et al identified TRPV6 in 1999 from rat duodenum in an effort to search for Ca2+ transporting proteins involved in Ca2+absorption. 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 and mouse orthologs of TRPV6 were cloned by Peng et al and Weber et al, respectively. The name TRPV6 was confirmed in 2005.
Gene location, chromosomal location, and phylogeny 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. In contrast to most other proteins, which initiate translation with an AUG codon, TRPV6 translation is initiated by non-AUG-codon-mediated reading. 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. However, it is still to be determined whether the long version of the TRPV6 protein is the dominant form in different tissues.
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. 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. 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. Two alleles of the TRPV6 gene have been identified in humans (originally noted as CaT-La and CaT-Lb). These alleles exhibit coupled polymorphisms generating two versions of the same gene. The polymorphisms give rise to an "ancestral variant" and a "derived variant" that differ in five bases and three amino acids. The ancestral allele codes for C197(157, in parentheses are annotated amino acid numbering), M418(378), and M721(681) whereas the derived allele codes for R197(157), V418 (378) and T721(681). The frequency of the ancestral TRPV6 allele varies across different population groups. It is hypothesized that selection pressures that could have changed TRPV6 allele distribution include changes in patterns of milk consumption, domestication of animals, change in ultraviolet light exposure due to trans-equatorial migration, genomic adaptations providing immune advantages to populations encountering new pathogens.
Tissue distribution 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 mainly confines on the apical membrane of epithelial cells. In the intestine, the protein is expressed on the brush-border membrane of enterocyte. Differences in the TRPV6 expression profile have been reported possibly due to variation in assay-dependent such primer design, hybridization probes, PCR vs. northern blotting, semi-quantitative PCR vs. RT-PCR, and antibodies used for immunodetection. 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 rodents, TRPV6 expression has been validated in the duodenum, cecum, small intestine, colon, placenta, pancreas, prostate, and epididymis by Northern Blotting. 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.
Structure and biophysical properties
Primary and secondary structure
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