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1 Genome Informatics and Analysis
2 Virology and Vaccine Systems
3 Ion Channel Section
4 Molecular Recognition
5 Molecular Genetics, Glaxo Wellcome Research and Development, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY
6 Peripheral Neuropathy Unit, Imperial College School of Medicine, Hammersmith Hospital, London W12 OHN, United Kingdom
7 Neural Plasticity Research Group, Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02129
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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dorsal root ganglia; capsaicin; autonomic nervous system; expressed sequence tag
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Subsequent to the identification of VR1, several related family members have been cloned, all of which share a similar topology to the Osm-9-like transient release potential (TRP) family of store-operated calcium channels (14). The second family member to be isolated was cloned from rat brain and was termed vanilloid receptor-like protein-1 (VRL-1) sharing 49% amino acid identity to VR1 (8). Unlike VR1, VRL-1 is not activated by vanilloids like capsaicin or RTX, nor by acidic pH or moderate heat. Instead, VRL-1 has been proposed to respond to high temperatures, having a threshold of 
52°C (8). In contrast to the specific neuronal localization of VR1, VRL-1 is widely expressed throughout the body, although in the DRG expression is restricted to non-VR1-expressing medium and large-diameter sensory neurones, with myelinated axons (8). A corresponding human VRL-1 ortholog was isolated from a myeloid cell line, followed by an independently identified mouse ortholog defined as a growth factor-regulated channel, or GRC (18)
The VR1 family has recently been extended to include two new members, one of which has been postulated to encode a mechanoresponsive stretch-inhibitable cation (SIC) channel and the other a truncated form of VR1 (VR.5'sv) (28, 24). The SIC channel, although highly homologous to VR1, lacks part of the NH2-terminal domain spanning the ankyrin repeat elements and, as well, possesses a different intracellular carboxyl terminal (28). This receptor was detected in both kidney and liver, with the channel being activated by cell shrinkage and inhibited by cell swelling (28). The truncated VR.5'sv clone was detected in DRG, brain, and peripheral blood leukocytes; however, it failed to respond to capsaicin, RTX, or noxious heat, thus implicating involvement of the NH2 terminus of VR1 in these functions (24). The least homologous channels in this family of receptors are known as the calcium transport protein (CaT1) and epithelial calcium channel (ECaC). The former receptor has been detected in the rat duodenum, proximal jejunum, cecum, and colon (22), whereas the latter was expressed in rabbit small intestine, kidney, and placenta (15). Calcium influx via these channels was voltage dependent and pH sensitive, exhibiting inhibition by low pH. Human orthologs for both genes with 80.5% identity to each other have been identified in the EMBL database.
We now describe the cloning, characterization, and tissue distribution of a novel vanilloid-like receptor isolated from human kidney, which we name VRL-2. Localization of VRL-2 to sympathetic nerves as well as nonneuronal cells lining the respiratory tract and kidney distal tubules suggests that vanilloid-like receptors have functions other than as sensory transducers in primary sensory neurons.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Full-Length Cloning
Human kidney was used as a source of template for the PCR amplification of VRL-2. Primers used for amplification were designed to isolate the gene in three fragments. Primers designed to isolate the 5' end included a sense primer encoding a NotI site and a strong Kozak motif followed by gene-specific sequence (5'-GTCATAGCGGCCGCGCGCCACCATGCCCAGGGTAGTTGGAC) and antisense primer (5'-CACCTCTTGTTGTCACTGGA). The middle fragment was PCR generated using sense and antisense primers 5'-CAAATCTGCGCATGAAGTTCCAG and 5'-GCCACGAGAAGTTCCACGTAGTG, respectively. Finally the 3' fragment was amplified with a sense primer 5'-GCTGCTCCCATTCTTGCTGA and an antisense primer 5'-TGCACTCTCGAGAAATGAGTGGGCAGAGAAGC encoding a XhoI restriction site. Amplified fragments were cloned into pCRII-TOPO according to the manufacturers instructions supplied with the TOPO TA Cloning kit (Invitrogen). Resulting clones for each of the three PCR generated VRL-2-fragments were taken for sequence analysis, and separate clones coding a consensus sequence were used in the full-length assembly of the gene into the pBluescript SK(+) vector (Stratagene). A consensus clone was then digested with NotI/XhoI and ligated into the mammalian expression vector pCDNA3.1(+) (Invitrogen).
Chromosomal Mapping by Radiation Hybrid Mapping
PCR primers 5'-ATGGCCACCAGGAGGGTTAC (sense) and 5'-TCTGCCAGGTTCCAGCTG (antisense) were designed to amplify a section of VRL-2 spanning part of the 3' coding region and 3'-UTR. PCR conditions for these primers were optimized using genomic DNA initially as template. PCR was then accomplished using both the somatic hybrid panel from Coriell Cell Repositories (Camden, NJ) and the Stanford G3 radiation hybrid panel from Research Genetics (Huntsville, AL). Amplification products were analyzed on a 2% agarose gel noting the presence or absence of specific bands in each well. Information collected from the G3 radiation hybrid panel was analyzed using the public web server at Stanford University (http://shgc-www.stanford.edu).
Fluorescence In Situ Hybridization
Fluorescence in situ hybridization (FISH) analysis using the VRL-2 PAC clone as a probe was performed according to Lichter et al. (19).
Localization of VRL-2 Expression
The following primers (5'-ACAAGAAGGCGGACATGCGG and 5'-ATCTCGTGGCGGTTCTCAAT) were used to obtain a PCR product from the coding region of VRL-2 to a region located upstream of transmembrane 1. This amplicon was used as a probe on multi-tissue Northern blots and dot blots (Clontech). Membranes were hybridized for 4 h shaking at 60°C in a 10% dextran sulfate, 1% SDS and 1 M NaCl solution. The probe was labeled with [
32-P]dCTP (Amersham) using the Rediprime DNA labeling system (Amersham), so as to obtain 500,000 cpm of the labeled probe per ml of prehybridization solution. A quantity of 100 ng of probe was boiled for 3 min (denaturization) and then cooled on ice for 2 min in a total volume of 45 µl. This was added to the labeling tube from the kit together with 3 µl of [32P]dCTP followed by an incubation at 37°C for 30 min. A volume of 400 µl of herring sperm DNA (Sigma) at a concentration of 8 µg/ml was added to the labeled probe and heated at 99°C for 3 min followed by rapid cooling on ice. The labeled probe was added and mixed well in prehybridization solution. The membranes were hybridized overnight at 55°C. The membranes were then washed, first at room temperature in 2x SSC and 1% SDS for 5 min, followed by 2x SSC and 1% SDS for 30 min at 50°C. If necessary, further washes with 1x SSC and 0.5% SDS or 0.1x SSC and 0.1% SDS for 30 min at the same temperature were carried out. The membranes were then exposed to Scientific Imaging Film AR (Kodak) using intensifying screens at -70°C overnight, and the film was developed.
Design and Production of Anti-VRL-2 Antibodies
The peptide CDGHQQGYPRKWRTDDAPL was synthesized by standard solid-phase techniques, purified by gel-filtration chromatography and used to generate antibodies as detailed in Amaya et al. (2).
Immunocytochemical Localization
Wax sections.
Lung (n = 1), trachea (n = 1), and kidney (n = 1) sections were fixed in neutral buffered formalin and processed to paraffin wax. Paraffin-embedded wax blocks were sectioned at 5 µm and underwent a microwave antigen retrieval procedure using a citrate buffer at pH 6.0 prior to immunostaining. Endogenous peroxidase was blocked with 3% hydrogen peroxide in water followed by nonspecific protein blocking in 5% milk powder in PBS. Sections were then incubated in the anti-VRL-2 antibody at room temperature for 1 h, followed by goat anti-rabbit (Biogennex) link antibody for 20 min. Finally, horseradish peroxidase-conjugated streptavidin (Biogennex) was applied to all sections and incubated for a further 20 min. Sections were visualized using 3,3'-diaminobenzidine (DAB) and counterstained briefly in Mayer’s hematoxylin prior to microscopic examination.
Cryostat sections.
Other human tissues tested included intestine, skin, nerve, temporal arteries, DRG, and sympathetic (stellate) ganglion. The tissues were skin from abdomen (n = 3), temporal arteries (n = 2), colon (n = 6), injured peripheral nerve (n = 3), DRG (n = 3), and sympathetic ganglion (n = 1). These tissues were collected at surgery (other than DRG and sympathetic ganglion, which were collected within 48 h postmortem), snap frozen in liquid nitrogen, and then embedded in OCT medium (RA Lamb) or immersed in 4% wt/vol paraformaldehyde in PBS overnight. After washing in PBS containing 15% wt/vol sucrose and 0.1% wt/vol sodium azide as cryopreservative, immersion-fixed sympathetic ganglia were further dissected and embedded in OCT as above. Frozen, 10-µm sections were collected onto poly-L-lysine-coated glass slides. Unfixed sections were postfixed in 4% wt/vol paraformaldehyde in PBS then washed in PBS. All tissue sections were incubated in 0.3% vol/vol hydrogen peroxide in methanol for 25 min to block endogenous peroxidase activity, then washed in PBS. Primary antibodies were diluted from 1:50 to 1:5,000 (optimum 1:800 for postfixed and 1:100 for prefixed) in PBS containing normal goat serum (1:30), and 0.01% sodium azide was then applied to tissue sections overnight. On the second day, tissues sections were washed in PBS, and secondary biotinylated antibodies were applied for 40 min. Sites of antibody attachment were revealed using avidin-biotin-peroxidase complex (ABC, Vector Laboratories) according to the method of Shu et al. (26). Positive control preparations were immunostained with mouse anti-peripherin (Novocastra Laboratories) to label enteric neurons.
Negative control preparations for all immunolocalization studies included replacement of primary antibodies with nonimmune rabbit serum, incubation in PBS only, or preincubation of primary antibodies with the corresponding immunizing peptide prior to immunostaining.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Sequencing of the EST clones and further in silico clustering enabled the generation of a 583-amino-acid single contig with 51.5% amino acid identity to rat VR1. To identify the full-length sequence, a genomic clone was isolated by PCR screening of a bacteriophage PAC genomic library. This clone was used to generate a mini-genomic library, which was sequenced to generate a single contig encoding the genomic sequence of this novel vanilloid-like receptor. The resulting full-length gene, which we have named human vanilloid receptor-like protein-2 (VRL-2), contains an open-reading frame (ORF) of 2,889 nucleotides that encodes a protein of 963 amino acids. The predicted transmembrane topology of this receptor is similar to that encoded by the rat VR1 gene (Fig. 1). The cytoplasmically located NH2-terminal of VRL-2 is 565 amino acids long and possesses three ankyrin-repeat domains, one possible cAMP/cGMP-dependent protein kinase phosphorylation site, and seven potential protein kinase C phosphorylation sites. This is followed by six transmembrane spanning domains (TMs) with a potential N-linked glycosylation site and an additional short hydrophobic stretch resembling a putative pore loop region present between TM5 and TM6. The cytoplasmically located carboxyl domain consists of 152 amino acids, which is almost identical to the corresponding domain in a related family member cloned from rat kidney, denoted SIC. Interestingly, the transmembrane domains of the SIC clone are identical to rat VR1. An alignment of VRL-2 with six other members of this proposed cation channel family is displayed in Fig. 2. The sequence has been shaded according to similarity across the subunits with topology also highlighted. VRL-2 appears to be most similar to the rat SIC channel, sharing 60% amino acid identity. VR1 and VRL-1 share 46% and 43% amino acid identities with VRL-2, respectively, with the more divergent members of the family, ECaC and CaT1, both sharing 28% identity.
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3.7 kb with highest levels detected in the trachea and kidney, followed by the pancreas, placenta, and prostate (Fig. 4). Dot blots corroborate these findings with a high-stringency signal recorded in trachea and salivary gland followed by kidney and lower levels existing in liver, placenta, fetal kidney, prostate, and lung. We were unable to detect VRL-2 expression in human DRG tissue by RT-PCR (data not shown).
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101–107 kDa, is detected upon exposure to the anti-VRL-2 antibody. In wells that were loaded with VR1 and VRL-1 transfected HEK cell lysates no antibody cross-reactivity or nonspecific interactions were detected. This anti-VRL-2 antibody was used to examine the VRL-2 expression pattern at a cellular level within the kidney cortex, along the respiratory tract, skin, sweat glands, and sympathetic ganglion. Figure 6 displays various sections taken from the kidney cortex with VRL-2-specific labeling restricted to the cells making up the distal tubules (Fig. 6, A and B). Expression is also detected in neutrophils present in the kidney (Fig. 6B). Immunostaining in trachea and lung sections was localized to the epithelial linings of both trachea and lung airways (Fig. 6, C and D) as well as serous cells of submucosal glands (Fig. 6E) and mononuclear cells (Fig. 6F).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Using chromosomal mapping techniques, we have localized VRL-2 to chromosome 12q23–24.1. Significant linkage data exists between this region of chromosome 12 and bipolar affective disorder (11). We also mapped the VR1 gene to chromosome 17p13, and this has been supported by the isolation of a bacterial artificial chromosome (BAC) clone (AF168787) from the same region, which contains genomic sequence encoding human VR1 (29). Sequence homologous to the carboxy terminal of the SIC channel was not found to be present on the AF168787 BAC clone. Extrapolation of these findings would suggest that the SIC channel may be the result of mRNA trans-splicing events from VR1 transcripts produced from chromosome 17 and VRL-2 transcripts from chromosome 12. Precedents for such events are rare in mammalian systems. However, one example includes the trans-splicing of the sensory neuronal-specific sodium channel (SNS) following exposure to nerve growth factor (NGF) (1). Using RT-PCR, we were unable to detect a corresponding human SIC channel in kidney, when using primers designed to amplify a region spanning the junction between VR1 and VRL-2 sequence (primer sites displayed in Fig. 3B). RT-PCR studies in rat kidney to amplify the SIC channel have been previously noted (20). This however, was achieved using primers that spanned the VRL-2 matching sequence; thus the amplification product could represent a novel, rat VRL-2 ortholog.
We carried out a range of experiments on VRL-2 cDNA, recombinantly expressed in HEK293T cells designed to elicit its potential functional role. However, all known gating stimuli for this family of channels (i.e., exposure to vanilloid molecules, noxious heat, acid and alkaline pH) neither generated inward currents or detectable calcium influx (data not shown). Experiments exploring the response to a range of pH values have revealed activation of ECaC (15, 16) and the rat ortholog CaT-1 (22) by alkali conditions and inhibition by acidic conditions. At hyperpolarizing potentials, ECaC is maximally activated, whereas under depolarizing conditions, ECaC-mediated Ca2+ influx rapidly diminishes. In addition, intracellular Ca2+ ions appear to play a direct role in regulation of the channel (16). Similarly, the structurally related TRP family of receptors has been proposed to mediate the entry of extracellular Ca2+ into cells in response to depletion of intracellular Ca2+ stores (5). A mouse TRP-like channel protein, OTRPC4, has recently been reported that responds to changes in extracellular osmolarity (27). This OTRPC4 channel, like VRL-2, did not respond to vanilloid molecules or to high temperature. Because of the inability of VRL-2 to respond to any known vanilloid-like receptor stimuli, it is possible that the protein may act in combination with an auxiliary subunit or indeed may respond optimally when coexpressed as a heteromultimer with another member of the vanilloid receptor family. An example that supports such a hypothesis is the 5-HT3B subunit, which has to associate with the 5-HT3A subunit to form a functional serotonin-gated calcium channel (9, 10).
A combination of RNA dot blotting and Northern blotting experiments demonstrated that VRL-2 mRNA is most abundant in trachea, salivary gland, and kidney. We were unable to detect VRL-2 mRNA in either rat or human DRG tissue. To further investigate the localization of VRL-2, we developed polyclonal antibodies directed to the COOH terminus and without any cross-reactivity against recombinantly expressed VR1 and VRL-1 proteins. Immunohistochemical experiments demonstrated localization of VRL-2 to the apical membranes of the trachea and lung airways and to the distal tubule of the kidney. It is interesting that the distal tubule is the only part of the nephron where calcium absorption occurs exclusively through a transcellular pathway, as opposed to paracellular passage, with the latter process occurring throughout the rest of the nephron (12). Localization of this subunit to the distal tubules is also a characteristic shared by rabbit ECaC (15). As ECaC shares a 28% amino acid identity with VRL-2, it is likely that a corresponding ECaC ortholog exists in humans. In support of this suggestion, a homology search using the ECaC sequence with the EMBL database reveals the existence of a human kidney ortholog that shares 84% amino acid identity with rabbit ECaC (21).
Intriguingly, the distribution and character of VRL-2 immunoreactivity in some peripheral organs (skin, blood vessels, intestine, and nerve) suggested its presence in autonomic but not in sensory fibers. The innervation of the arrector pili smooth muscle in skin is sympathetic, with coexpression of noradrenaline and neuropeptide Y (NPY) causing piloerection (6). Postganglionic sympathetic adrenergic fibers also innervate skin blood vessels and cause vasoconstriction (3). The innervation of sweat glands is cholinergic sympathetic; these fibers co-release acetylcholine and vasoactive intestinal peptide (VIP). The pattern of VRL-2 staining in the gut suggests its presence both in sympathetic and parasympathetic fibers but not in intrinsic gut neurons.
The VR1 receptor functions as a peripheral transducer of painful thermal stimuli, which is potentiated by drops in pH, encouraging influx of calcium at reduced temperatures. The structurally related ECaC, VRL-1, and SIC receptors have functional responses that are modified by pH, high heat, and osmotic stretch, respectively, suggesting that this family of receptors may provide mammals with a defense mechanism against diverse physical stimuli. The currently unknown functional roles of VRL-2 in the kidney, airway epithelia, and nerve fibers deserve further investigation to establish whether it, too, participates in a defense mechanism or has some quite different role in regulating ion flux in these diverse tissues.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. N. Tate, Ion Channel Section, Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK (E-mail: st6707{at}glaxowellcome.co.uk).
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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