Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line.

Gorn, Alan; Lin, Herbert Y.; Yamin, Moshe; Auron, Philip E.; Flannery, Merrilee R.; Tapp, David R.; Manning, Catherine A.; Lodish, Harvey F.; Krane, Stephen M.; Goldring, Steven R.

doi:10.1172/jci116046

Cited by 190 publications

(78 citation statements)

References 49 publications

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“…These data are consistent with photocross-linking to the amino terminus of the mutant receptor with cleavage at Met 49 and confirm Met 49 as the site of cross-linking for [Bpa 8 ]sCT (8 -32) (Fig. 7C) 19 ]sCT (8 -32) efficiently labeled the HA-hCTR a receptor transiently expressed in COS-7 cells with a single radioactive band of M r ϳ97,000, which shifted to M r ϳ52,000 after Nglycosidase F deglycosylation (Fig. 8A).…”

Section: Pharmacological Characterization Of the Antagonist Peptidesupporting

confidence: 84%

“…Antagonism of hCT-induced cAMP production by sCT (8 -32) Fig. 2, BϪD 19 ]sCT(8 -32)) with high affinity, similar to that seen for unmodified sCT (Fig. 3, A and B).…”

Section: Pharmacological Characterization Of the Antagonist Peptidesupporting

confidence: 62%

“…Of these, the members of the teleost/avian group are generally the most potent, although relative potency varies in a species-and isoform-specific manner (19,(27)(28)(29)(30)(31). The higher potency combined with a longer in vivo half-life has led to fish-like CTs, exemplified by salmon CT (sCT), being the principle form of CT used for the clinical treatment of bone disorders (32, 33).…”

Section: Calcitonins (Cts)mentioning

confidence: 99%

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Insights into Interactions between the α-Helical Region of the Salmon Calcitonin Antagonists and the Human Calcitonin Receptor using Photoaffinity Labeling

Pham

Dong

Wade

et al. 2005

Journal of Biological Chemistry

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Fish-like calcitonins (CTs), such as salmon CT (sCT), are widely used clinically in the treatment of bone-related disorders; however, the molecular basis for CT binding to its receptor, a class II G protein-coupled receptor, is not well defined. In this study we have used photoaffinity labeling to identify proximity sites between CT and its receptor. Calcitonins (CTs)1 are 32-amino acid peptide hormones with a wide spectrum of biological activity. The most recognized action is the inhibition of osteoclast-mediated bone resorption, which forms the basis for its primary clinical use in the treatment of bone-related disorders such as Paget disease, osteoporosis, and hypercalcemia of malignancy (1-3). CT, however, also has activity that includes modulation of renal ion excretion (4 -7), analgesia (8), inhibition of appetite (9), and gastric acid secretion (10 -12), as well as effects on reproduction via effects on embryological implantation and sperm function (13-15).Calcitonin receptors (CTRs) belong to the class II subfamily of G protein-coupled receptors, which also includes receptors for other peptides such as parathyroid hormone (PTH) and PTH-related peptide, secretin, vasoactive intestinal peptide, glucagon, glucagon-like peptide-1, growth hormone-releasing hormone, calcitonin gene-related peptide, and corticotropinreleasing factor. These peptide hormone class II G proteincoupled receptors share 30 -50% amino acid identity as well as a number of conserved structural motifs and are thought to interact with their ligands in a similar manner (16 -18).Alternative RNA splicing yields multiple CTR mRNA isoforms. In man, at least six potential variants exist (19 -26); however, the most common hCTR isoforms differ by the presence (hCTR b ) or absence (hCTR a ) of a 16-amino acid insert between amino acids 174 and 175, within the first intracellular loop of the receptor (23). Of these, the hCTR a is the major human receptor isoform and is expressed in essentially all tissues known to express the CTR.CTs from different species can be subdivided into three major classes: human/rodent, artiodactyl, and teleost/avian. Of these, the members of the teleost/avian group are generally the most potent, although relative potency varies in a species-and isoform-specific manner (19,(27)(28)(29)(30)(31). The higher potency combined with a longer in vivo half-life has led to fish-like CTs, exemplified by salmon CT (sCT), being the principle form of CT used for the clinical treatment of bone disorders (32, 33).However, the usefulness of CT is limited by the development of clinical resistance. This can be due to the development of circulating antibodies against non-human CT (34 -38), but it also occurs from loss of responsiveness to CT, presumably via receptor down-regulation and inhibition of new receptor synthesis (39 -41). The optimal use of CTs remains unresolved, a situation that stems in part from lack of understanding of the bimolecular interaction between CT and its receptor and how

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Section: Pharmacological Characterization Of the Antagonist Peptidesupporting

confidence: 84%

“…Antagonism of hCT-induced cAMP production by sCT (8 -32) Fig. 2, BϪD 19 ]sCT(8 -32)) with high affinity, similar to that seen for unmodified sCT (Fig. 3, A and B).…”

Section: Pharmacological Characterization Of the Antagonist Peptidesupporting

confidence: 62%

Section: Calcitonins (Cts)mentioning

confidence: 99%

See 1 more Smart Citation

Insights into Interactions between the α-Helical Region of the Salmon Calcitonin Antagonists and the Human Calcitonin Receptor using Photoaffinity Labeling

Pham

Dong

Wade

et al. 2005

Journal of Biological Chemistry

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“…[23][24][25][26] CT binds two G-protein-coupled receptors in humans: CT receptor types 1 (CT (A) ) and 2 (CT (B) ). [27][28][29] CT (A) and CT (B) are both associated with the heterotrimeric G-protein Gs and increase intracellular cAMP, but CT (B) can also affect phosphoinositide-specific phospholipase C. 30 Although CT affects several organs, its principal target is the kidney where it is largely degraded. [31][32][33][34][35][36] The distribution of CT-binding sites is slightly different among rat, mouse, rabbit, primate, and human.…”

mentioning

confidence: 99%

Calcitonin Has a Vasopressin-like Effect on Aquaporin-2 Trafficking and Urinary Concentration

Bouley¹,

Lu²,

Nunes³

et al. 2011

Journal of the American Society of Nephrology

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The most common cause of hereditary nephrogenic diabetes insipidus is a nonfunctional vasopressin (VP) receptor type 2 (V2R). Calcitonin, another ligand of G-protein-coupled receptors, has a VP-like effect on electrolytes and water reabsorption, suggesting that it may affect AQP2 trafficking. Here, calcitonin increased intracellular cAMP and stimulated the membrane accumulation of AQP2 in LLC-PK1 cells. Pharmacologic inhibition of protein kinase A (PKA) and deficiency of a critical PKA phosphorylation site on AQP2 both prevented calcitonin-induced membrane accumulation of AQP2. Fluorescence assays showed that calcitonin led to a 70% increase in exocytosis and a 20% decrease in endocytosis of AQP2.Immunostaining of rat kidney slices demonstrated that calcitonin induced a significant redistribution of AQP2 to the apical membrane of principal cells in cortical collecting ducts and connecting segments but not in the inner stripe or inner medulla. Calcitonin-treated VP-deficient Brattleboro rats had a reduced urine flow and two-fold higher urine osmolality during the first 12 hours of treatment compared with control groups. Although this VP-like effect of calcitonin diminished over the following 72 hours, the tachyphylaxis was reversible. Taken together, these data show that calcitonin induces cAMP-dependent AQP2 trafficking in cortical collecting and connecting tubules in parallel with an increase in urine concentration. This suggests that calcitonin has a potential therapeutic use in nephrogenic diabetes insipidus.

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“…When translation initiates in E3a, it is possible that the N terminus of mCTR is cytoplasmic, with the adjacent sequence of hydrophobic residues forming an additional eighth transmembrane domain. Like mCTR, the hCTR mRNA has also been reported to contain two putative translation start sites (17), and the upstream start is contained within a variably spliced 71-bp exon (24). The translation product initiated from the hCTR upstream start site is 18 amino acids longer than if initiated from the downstream start site.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific and Ubiquitous Promoters Direct the Expression of Alternatively Spliced Transcripts from the Calcitonin Receptor Gene

Anusaksathien

Laplace

et al. 2001

Journal of Biological Chemistry

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The gene encoding the murine calcitonin receptor (mCTR) was isolated, and the exon/intron structure was determined. Analysis of transcripts revealed novel cDNA sequences, new alternative exon splicing in the 5-untranslated region, and three putative promoters (P1, P2, and P3). The longest transcription unit is greater than 67 kilobase pairs, and the location of introns within the coding region of the mCTR gene (exons E3-E14) are identical to those of the porcine and human CTR genes. We have identified novel cDNA sequences that form three new exons as well as others that add 512 base pairs to the 5 side of the previously published cDNA, thereby extending exon E1 to 682 base pairs. Two of these novel exons are upstream of exon E2 and form a tripartite exon E2 (E2a, E2b, and E2c) in which E2a is utilized by promoter P2 with variable splicing of E2b. The third new exon (E3b) lies between E3a and E3b and is utilized by promoter P3. Analysis of mCTR mRNAs has revealed that the three alternative promoters give rise to at least seven mCTR isoforms in the 5 region of the gene and generate 5-untranslated regions of very different lengths. Analysis by reverse transcription-polymerase chain reaction shows that promoters P1 and P2 are utilized in osteoclasts, brain, and kidney, whereas promoter P3 appears to be osteoclast-specific. Using transiently transfected reporter constructs, promoter P2 has activity in both a murine kidney cell line (MDCT209) and a chicken osteoclastlike cell line (HD-11EM), whereas promoter P3 is active only in the osteoclast-like cell line. These transfection data confirm the osteoclast specificity of promoter P3 and provide the first evidence that the CTR gene is regulated in a tissue-specific manner by alternative promoter utilization.

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Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line.

Cited by 190 publications

References 49 publications

Insights into Interactions between the α-Helical Region of the Salmon Calcitonin Antagonists and the Human Calcitonin Receptor using Photoaffinity Labeling

Insights into Interactions between the α-Helical Region of the Salmon Calcitonin Antagonists and the Human Calcitonin Receptor using Photoaffinity Labeling

Calcitonin Has a Vasopressin-like Effect on Aquaporin-2 Trafficking and Urinary Concentration

Tissue-specific and Ubiquitous Promoters Direct the Expression of Alternatively Spliced Transcripts from the Calcitonin Receptor Gene

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