Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

TRPV6

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101911

Synonyms

Historical Background

According to the nomenclature of transient receptor (TRP) channels TRPV6 represents the last member of the vanilloid-like TRP (TRPV) subfamily which were named after the first member TRPV1. TRPV1 can be activated by vanilloid-like compounds (Caterina et al. 1999; Montell et al. 2002). TRPV6 was first isolated from rat small intestine using a functional cloning approach (Peng et al. 1999). The human orthologue which shows only 90% identical amino acids to the rat sequence was cloned from a human placenta cDNA library (Wissenbach et al. 2001), and the mouse sequence was cloned by Hirnet and coworkers (Hirnet et al. 2003).

Properties of the TRPV6 Channel

The functional TRPV6 channel consists of four identical subunits, the four TRPV6 proteins, which form a protein complex of more than 340 kDa. Recently the crystal structure of the TRPV6 channel complex has been elucidated at 3.25 Å (Saotome et al. 2016). One TRPV6 subunit offers six transmembrane segments TM1 to TM6 (Figs. 1 and 2). The tetrameric channel can be modified by N-Glycosylation which occurs only in the extracellular loop between TM1 and TM2 (Chang et al. 2005; Hirnet et al. 2003; Hoenderop et al. 2003). The pore-forming region is formed by TM5, the linker, and TM6. Within the pore region an aspartate residue D582 determines the calcium selectivity of TRPV6 (Nilius et al. 2001b). Mutation of D582A leads to a calcium impermeable channel. This finding is supported by the crystal structure which shows that the four aspartate of each of the four TM5-TM6 linkers form a circle of the upper gate of the channel (Saotome et al. 2016). The same amino residue is the target for intracellular magnesium which acts as an open channel blocker from the cytosolic side (Voets et al. 2003). TRPV6 currents can be seen by reducing the extracellular calcium concentration and adding Ca2+ ions from the outside. After calcium addition an inwardly rectifying calcium selective current can be observed, PCa/PNa > 100 (Peng et al.2000; Vennekens et al. 2000). This current quickly inactivates by yet not identified calcium-dependent mechanism. Thus TRPV6 currents can be recorded only in the presence of strong intracellular calcium buffering. In the absence of extracellular calcium TRPV6 channels are permeable for monovalent ions like Na+, but the currents are about ten times larger than those observed for calcium ions. Single channel conductance, which was only estimated for the sodium conductance, is in the range of 40 to 70 pS (Vassilev et al. 2001; Yue et al. 2001). Other divalent ions can also permeate TRPV6 in the order Ca2+>Ba2+>Sr2+>Mg2+ (Peng et al. 2000; Vennekens et al. 2000). The cytosolic C-terminal part of TRPV6 contains six ankyrin-like repeats which are in part involved in the assembly of the channel subunits (Erler et al. 2004; Wissenbach et al. 2001). The N-terminal region contains a high affinity calmodulin binding site which facilitates the inactivation of TRPV6 in the presence of Ca2+ (Niemeyer et al. 2001). Within the calmodulin binding site phosphorylation of a threonine by protein kinase C counteracts calmodulin binding.
TRPV6, Fig. 1

Structure of TRPV6 View on the surface of the TRPV6 channel. Four subunits form a functional TRPV6 channel. The Ca2+selectivity filter of the ion channel consists of four aspartate residues (red) which are located in the pore region (McNicholas et al. 2011; Saotome et al. 2016)

TRPV6, Fig. 2

Features of TRPV6 TRPV6 contains six transmembrane (TM) domains with a pore loop between TM5 and TM6. Within the pore region an aspartate residue (D) is responsible for the calcium selectivity (Nilius et al. 2001b; Weissgerber et al. 2011). Translation of the TRPV6 protein is initiated at an ACG triplet, which is translated into methionine, 120 bp upstream of the first AUG triplet in frame. The N-glycosylation at N397 within the first extracellular loop is substrate for the ß-glucoronidase klotho which stabilizes the channel in the plasma membrane (Chang et al. 2005). The linker between TM4 and TM5 (S4-S5 linker) is conserved among many TRP proteins and a number of mutations within this region lead to constitutive open channel formation (Hofmann et al. 2016). Also a conserved region downstream of TM6, the TRP motive (purple) is involved in the gating mechanism (Caterina et al. 1999; Montell et al. 2002). In humans two TRPV6 alleles are known (*) an ancestral variant which encodes the amino acids R197, V418, and T721 whereas the TRPV6b variant exhibits at the corresponding positions the amino acids C197, M418, and M721. Typically these polymorphisms are coupled (Kessler et al. 2009; Wissenbach et al. 2001)

Pharmacology

TRPV6 currents can be blocked by the trivalent ions La3+ and Gd3+ in the micromolar range (Peng et al. 1999), by Xestospongin a natural isolate of a sponge (Vassilev et al. 2001) and by the antimycotic drugs econazole and miconazole as well as by ruthenium red (Hoenderop et al. 2001; Nilius et al. 2001a; Schwarz et al. 2006). Also a synthetic compound TH-1177 is supposed to inhibit TRPV6 currents with an IC50 of 0.44 μM (Haverstick et al. 2000; Landowski et al. 2011). 2-APB, a rather nonspecific modulator of TRP channels, inhibits TRPV6 (Kovacs et al. 2012). Soricidin a toxic peptide derived from saliva of short-tailed shrew inhibits currents although inhibition is not complete (Bowen et al. 2013). No specific activator of TRPV6 currents is known.

Expression Pattern

The expression of the TRPV6 gene seems to be not completely identical within different species. The murine TRPV6 is expressed in placenta, pancreas, salivary gland (Hirnet et al. 2003), epididymis (Weissgerber et al. 2011), prostate, and small intestine (Muller et al. 2000). In addition TRPV6 is expressed in bone marrow cells (Nijenhuis et al. 2003). In contrast, in humans TRPV6 expression in small intestine has never been shown convincingly and human prostate does not express TRPV6 transcripts, but TRPV6 is upregulated in prostate cancer (Fixemer et al. 2003; Wissenbach et al. 2004; Wissenbach et al. 2001); for details see the section “disease relation.”

Genomic Inactivation and Physiological Consequence

The TRPV6 gene was inactivated by gene targeting by three independent strategies, and the results obtained from these KO mice are overlapping but not completely identical. Replacing of the TM 2–6 region, the C-terminus, and part of the adjacent tail to tail located EphB6 receptor gene corresponding to exon 9–15 by a neo cassette led to growth retardation, reduction of body weight, reduced fertility of male and female mice, increased renal calcium secretion, polyuria, alopezia, and dermatitis (Bianco et al. 2007). In another approach the transmembrane domains with the pore-forming region and the complete cytosolic C-terminus were deleted by a Cre-lox strategy (exon 13–15, see Fig. 3) as well as part of the adjacent EphB6 gene (Weissgerber et al. 2012). These mice show hypofertility of the male but not the female mice. The reduced fertility of the male mice was found to depend on the inactivation of TRPV6 within the apical membrane of the epididymis resulting in an increased luminal calcium concentration which leads to reduced motility of the sperms. Two mouse lines originated from independent ES clones were analyzed and showed an identical phenotype. But these KO mice lines do not show increased renal calcium secretion, alopezia, and dermatitis. Also the body weight wasn’t reduced. A third KO mouse was generated by replacing exon2 with a neo cassette. These mice showed reduced body weight and a disturbed bone microarchitecture caused by impaired osteoclast differentiation (Chen et al. 2014).
TRPV6, Fig. 3

Genomic locus of the TRPV6 gene The TRPV6 gene codes 15 exons (upper trace) and is adjacent to the TRPV5 and the ephrine receptor B6 (EphB6) genes; KEL Kell blood group antigen, ORF open reading frame (lower trace)

Furthermore, a knock-in mouse line was generated, in which the amino acid within the pore region responsible for Ca2+ selectivity, (D582A), was replaced by an alanine resulting in a dead channel (Weissgerber et al. 2011). These mice show an identical phenotype like the mice carrying the deletion of exons 13–15 (Weissgerber et al. 2012). This knock-in mouse was also used to generate a TRPV6 KO mouse by deleting exon 13–15, and it showed an almost identical phenotype.

The reason that independent groups found different phenotypes is not clear but one might speculate that the inactivation strategy as well as strain-based differences might have an influence on the result. Inactivation of the EphB6 receptor did not lead to one of the phenotypes described above (Luo et al. 2004).

Taking together, male hypofertility is the most robust phenotype found in TRPV6 KO mice so far.

Disease Relation

TRPV6 transcripts were found to be overexpressed in the most common cancers of humans namely prostate (Fig. 4) and breast cancer (Bolanz et al. 2008; Bolanz et al. 2009; Fixemer et al. 2003; Wissenbach et al. 2004). In addition TRPV6 was detected in malignancies of the colon, thyroid, ovarian, and endometrium (Bowen et al. 2013; Wissenbach and Niemeyer 2007; Zhuang et al. 2002). In case of prostate cancer it was demonstrated that expression of TRPV6 is correlated with aggressiveness of the disease whereas in benign and healthy tissue TRPV6 transcripts could not be detected (Fixemer et al. 2003; Wissenbach et al. 2004; Wissenbach et al. 2001).
TRPV6, Fig. 4

Expression of TRPV6 in prostate cancer In situ hybridization of a human prostate cancer specimen (Gleason grade 8–9) using TRPV6 antisense oligonucleotides. TRPV6 positive cells are visualized by the brown color; nuclei are stained with hematoxylin

Evolution

TRPV6 and its next homolog TRPV5 which shows ∼75% identical amino acids are located in tandem on the human chromosome 7q33–35 which corresponds to the murine chromosome 6 and rat chromosome 4 (Hirnet et al. 2003; Hoenderop et al. 1999; Muller et al. 2000; Peng et al. 1999; Wissenbach et al. 2001). Nonmammalian animals contain only one TRPV5-/6-like gene which is slightly more similar to TRPV6. This indicates that TRPV5 and TRPV6 arose from gene duplication. TRPV5, which is mainly expressed in kidney, might be an adaptation to specific requirements of the secondary kidneys of mammalian animals (Peng 2011).

The dissimilarity of TRPV6 proteins from several species was compared to human TRPV6 and plotted versus time (Fig. 5). From this molecular clock it can be concluded that TRPV6 has a constant mutation rate resulting in ∼0.9 amino exchange per 1 million years and arose from a precursor around 730 million years ago.
TRPV6, Fig. 5

Molecular clock of TRPV6 The TRPV6 dissimilarity of mammalian and nonmammalian TRPV6 proteins compared to human TRPV6 was blotted versus time. Each point represents the branch point of the common ancestor of human/chimpanzee, human/mice, human/chicken, and so on

The TRPV6-related sequence of the green algae Chlamydomonas reinhardtii shows a clearly higher degree of homology to mammalian TRPV6 proteins as one would expect. From this finding one would speculate that the Chlamydomonas TRPV6 is the result of horizontal gene transfer at a late time point during evolution (Merchant et al. 2007).

One has to mention that in humans two alleles of TRPV6 are known; the ancestral form, TRPV6a which differs to TRPV6b by 3 amino acids, namely, R197V, V318M, and T721M (Wissenbach et al. 2001). The mammalian TRPV6 sequences of animals reflect the TRPV6a variant whereas the TRPV6b variant occurs exclusively in humans. With increasing distance to the African continent the allele frequency of TRPV6b increases with Asian populations being up to 97% homozygous for TRPV6b whereas homozygous TRPV6a individuals are hardly detectable. In contrast the TRPV6a allele frequency increases in African population from north to south resulting in up to 85% TRPV6a alleles (Akey et al. 2006). The reason for this unequal distribution is not clear since TRPV6a and TRPV6b show very similar electrophysiological properties (Hughes et al. 2008). The TRPV6b variant is not present in apes and as calculated from the molecular clock one would estimate that the TRPV6b variant came up ∼2.7 million years ago. This is clearly after the split of human and apes around 4 million years ago (Pennisi 2006) and before the modern humans left Africa around 150.000 years ago and replacing the Neanderthals in Europe (Caramelli et al. 2003; Stringer and Andrews 1988).

Special Feature

The cDNA of the human TRPV6 was cloned from human placenta, and the translated cDNA sequence showed no in frame stop codon upstream of the first in frame AUG triplet (Wissenbach et al. 2001). Translation of the whole cDNA sequence revealed that the amino acid sequences upstream of the first AUG codon is conserved among several mammalian species which is unusual. Fecher-Trost and coworkers studied if the translational start of TRPV6 is upstream of the first AUG triplet (Fecher-Trost et al. 2013). Indeed the TRPV6 translation starts exclusively at an ACG triplet 120 bp upstream of the first AUG triplet. MS data obtained by mass spectrometry show that this ACG triplet which would code threonine (T) is instead translated into methionine (M). The full length TRPV6 protein is slightly better transferred to the plasma membrane as the TRPV6 initiated at the first AUG codon. In fact this N-terminal-truncated TRPV6 does not occur in vivo. Nevertheless the electrophysiological properties of the full length TRPV6 channels formed from the full-length 765 aa protein is similar to channels formed by the truncated 725 aa variant.

Summary

The family of transient receptor potential, TRP, channels consists mostly of nonselective cation channels with the exception of TRPV6 and TRPV5 which are highly Ca2+ selective channels showing an ion conductance of PCa/PNa > 100. TRPV6 (and TRPV5) belong together with L-type calcium channels and CRAC channels (Orai/Stim) to the most calcium selective ion channels which are known. Genetic inactivation of the TRPV6 gene leads to hypofertility of male mice as the consequence of inadequate sperm maturation within the epididymis. In the human population two TRPV6 alleles are present which differ in three amino acids, TRPV6a and TRPV6b. The TRPV6 protein of apes reflects the human TRPV6a variant; thus human TRPV6b is one of the very rare proteins which is significantly different compared to higher primates. The translational start triplet of TRPV6 is an ACG codon which usually would be translated into threonine but instead is translated into methionine (Fecher-Trost et al. 2013). TRPV6 has a restricted expression pattern in humans and is most dominantly expressed in the human placenta, exocrine pancreas, and some exocrine gland tissues, but in addition, overexpressed in frequent malignancies as prostate and breast cancer (Bolanz et al. 2008; Fixemer et al. 2003; Wissenbach et al. 2004; Wissenbach et al., 2001). From these findings TRPV6 is a promising drug target for the treatment of several malignancies.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Experimental and Clinical Pharmacology and ToxicologySaarland UniversityHamburgGermany