CTRs from vertebrates were listed (E-Table 27A.3). The calcitonin receptor belongs to the B family of 7-transmembrane receptors and consists of seven transmembrane spanning domains with a long extracellular N-terminus and an intracellular C-terminus. Immunofluorescence was used to correlate binding and the presence of CGRP and its receptor components, calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), and the distribution of PACAP and glutamate in rhesus and rat TG. Deborah L. Galson, G. David Roodman, in Osteoimmunology, 2011. Specific prophylactic migraine treatments are urgently needed because of the unmet needs of many migraine patients. In mammals, the major source of calcitonin is from the parafollicular or C cells in the thyroid gland, but it is also synthesized in a wide variety of other tissues, including the lung and intestinal tract. (2003) demonstrated that the mouse calcitonin receptor gene, which is located in the proximal region of chromosome 6, is imprinted specifically in the brain, with predominant expression of the maternal allele. Three alternatively spliced Calcitonin Receptor isoforms have been identified. The CTR and other members of its family also interact with accessory proteins called receptor-activity-modifying proteins or RAMPs that act as allosteric modulators and can change the cellular location or binding specificity of the receptor. Honoo Satake, in Handbook of Hormones, 2016. The osteoclast is the primary target of calcitonin, but receptors also are present in the kidney, osteocytes, brain, testes, placenta, and lung [161]. findings show that human skin keratinocytes and fibroblasts express adrenomedullin and its receptors L1-R and CRLR. Calcitonin works to control calcium and potassium levels. One of these anti-CGRP monoclonal antibodies, erenumab (Aimovig™), has been approved by the Federal Drug Administration (FDA) and is now available for patients. Because of their structural similarity, they can cross-react at their cognate receptors. It may also affect the ovaries in women and the testes in men. Human calcitonin receptor polymorphisms have been identified in several different ethnic groups. As well as playing a role in cranial nociception [ 10 ], CGRP is a potent general arterial vasodilator. Calcitonin receptors have been described in many tissues throughout the body. The receptors of the other members of the family are made up of subunits. The calcitonin/CGRP family of peptides includes calcitonin,α and β CGRP, amylin, adrenomedullin (AM) and adrenomedullin 2/intermedin (AM2/IMD). The calcitonin receptor is encoded by the CALCR gene and comprises >90 kb and 14 exons.112 The complexity of CALCR is shared by other class II G protein–coupled receptors, and the structural organization and size of the human gene are similar to the pig CTR gene.123 Species differences include that the pig I1 insert is generated by selective use of alternate splice sites located on exon 8, while in humans, the I1 insert occurs on a separate exon, with at least one additional exon proximal to exon 7 in the pig.115 Isolation of the mouse CALCR124 revealed that the locations of introns within the coding region of the mCTR gene (exons E3 to E14) are identical to those of the porcine and human CTR genes. The osteoclast is the primary target of calcitonin, but receptors also are present in the kidney, osteocytes, brain, testes, placenta, and lung [210,213]. Three named splice variants are; P30988-1, P30988-2, P30988-3. Calcitonin receptor isoforms generated from alternative splicing have been described in a number of normal tissues and tumors.
An evidence describes the source of an annotation, e.g. 1 Location: 162 → 472 7tmB1_calcitonin_R; calcitonin receptor, member of the class B family of seven-transmembrane G protein-coupled receptors pfam02793 Location: 86 → 154 HRM; Hormone receptor domain; NM_007588.2 → NP_031614.2 calcitonin receptor isoform 1b precursor. The CTR does not require RAMPs to bind and respond to CT. Nobuo Suzuki, in Handbook of Hormones, 2016. The CALC1 gene comes from a superfamily of relevant healthy protein hormonal agent forerunners including island amyloid precursor healthy protein, calcitonin gene-related peptide, and the forerunner of adrenomedullin. It is one of the best differentiation markers for distinguishing mammalian osteoclasts from macrophage polykaryons. The interaction of this receptor with RAMPs may also be subtly different. Help pages, FAQs, UniProtKB manual, documents, news archive and Biocuration projects. 1994 Dec;135(6):2635-43 The overall effect of calcitonin is to lower the concentration of calcium in the blood when it rises above the normal value. S.I. It opposes the action of the parathyroid hormone, helping to regulate the blood’s calcium and phosphate levels. N Engl J Med. Calcitonin receptor activation leads to a rise in cAMP/PKA and PKC activity. 1 Each receptor is a heterodimer consisting of a receptor-activity-modifying protein (RAMP) and either the calcitonin receptor (CTR) or calcitonin receptor-like receptor (CLR) GPCR signaling subunit. Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have recently shown efficacy in episodic and chronic migraine and will be available soon. The association of the CTR with RAMPs 1, 2, and 3 functions as the AMY receptors. CT works by activating the G-proteins Gs and Gq often found on osteoclasts, on cells in the kidney, and on cells in a number of regions of the brain. Rimegepant, an Oral Calcitonin Gene-Related Peptide Receptor Antagonist, for Migraine. [10], Calcitonin receptor has been shown to interact with Apolipoprotein B[11][12] and LRP1. The osteoclast is the primary target of calcitonin, but receptors also are present in the kidney, osteocytes, brain, testes, placenta, and lung [161]. Some of these isoforms are nonfunctional and may have a regulatory effect by inhibiting calcitonin signaling [163]. Although the binding properties of this receptor are similar to the hCT(a) receptor, it is poorly internalized and has altered G-protein coupling. 112 The complexity of CALCR is shared by other class II G protein–coupled receptors, and the structural organization and size of the human gene are similar to the pig CTR gene. The CGRP receptor consists of three subunits: receptor activity-modifying protein 1 (RAMP1), calcitonin-like receptor (CLR) and receptor component protein (RCP) . 5. The peptide hormone calcitonion (CT) is the founding member of a family of peptides that comprises amylin (AMY), calcitonin gene-related peptides (CGRPα and CGRPβ), adrenomedullin (AM), intermedin (IMD), and calcitonin receptor-stimulating peptide (CRSP). P32214, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=protein& list_uids=16758660&dopt=GenPept, http://www.ensembl.org/ Mus_musculus/geneview?gene= ENSMUSG00000023964, http://ca.expasy.org/cgi-bin/niceprot.pl? Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome In the mouse, it is in the proximal region of chromosome 6, while the pig gene is located in chromosomal band 9q11 to 12. Nevertheless, Ci-CT elicits weak but significant cAMP production via human CTR expressed in COS-7 cells [1]. Different isoforms of CTR resulting from alternative splicing of the gene have been described in various animal species with differential tissue expression of the transcripts [6]. Calcitonin is one of those critical hormones. Calcitonin injection side effects. 4. John J. Wysolmerski, in Vitamin D (Fourth Edition), 2018. the calcitonin receptor (ctr) is a class B G protein-coupled receptor (GPCR). Debbie Hay, in xPharm: The Comprehensive Pharmacology Reference, 2007. The human CTR gene has been mapped to chromosome 7q21.3. Sequence archive. All of the major splice variants and polymorphisms for each species are discussed in the following comprehensive reviews: Sexton and others Sexton et al (1999), Poyner and others Poyner et al (2002). The calcitonin receptor, localized to osteoclasts, the kidney, and regions of the brain, is a G protein-coupled receptor. The ability of calcitonin–CTR interaction to block multinucleation was mimicked by both activating the cAMP–PKA pathway, and by activating the exchange protein directly activated by the cAMP (Epac) pathway. [13], transmembrane signaling receptor activity, calcitonin gene-related peptide receptor activity, positive regulation of adenylate cyclase activity, adenylate cyclase-activating G-protein coupled receptor signaling pathway, positive regulation of cytosolic calcium ion concentration, G-protein coupled receptor signaling pathway, positive regulation of protein kinase A signaling, positive regulation of peptidyl-serine phosphorylation, cross-receptor inhibition within G-protein coupled receptor heterodimer, positive regulation of protein kinase B signaling, positive regulation of ERK1 and ERK2 cascade, positive regulation of calcium ion import across plasma membrane, GRCh38: Ensembl release 89: ENSG00000004948, GRCm38: Ensembl release 89: ENSMUSG00000023964, "Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo", "Calcitonin receptor plays a physiological role to protect against hypercalcemia in mice", "Nascent lipidated apolipoprotein B is transported to the Golgi as an incompletely folded intermediate as probed by its association with network of endoplasmic reticulum molecular chaperones, GRP94, ERp72, BiP, calreticulin, and cyclophilin B", "Multiple molecular chaperones interact with apolipoprotein B during its maturation. Calcitonin gene-related peptide (CGRP) is a neuropeptide with a pivotal role in the pathophysiology of migraine. The calcitonin receptor (CT) is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis, particularly with respect to bone formation and metabolism. Other splice variants may lead to a nonfunctional protein, silent mutations, and N-terminal truncations. In birds, fish and amphibians, calcitonin is secreted from the ultimobrachial glands. Woodrow et al. Call your doctor at once if you have: Thus, CLR requires RAMP1 to function as a CGRP preferring receptor. Help. This receptor is of identical sequence to the hCT(a) receptor but contains a 16 amino acid insert in the first intracellular loop. Calcitonin receptors have been described in many tissues throughout the body. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. xPharm: The Comprehensive Pharmacology Reference, http://www.ensembl.org/Homo_sapiens/ geneview?gene=ENSG00000004948, http://kr.expasy.org/ cgi-bin/niceprot.pl?P30988;%20RefSeq %20NP_001733, http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?cmd=Retrieve&db= protein&list_uids=4502547&dopt=GenPept, http://www.ensembl.org/ Rattus_norvegicus/geneview?gene= ENSRNOG00000010053, http://ca.expasy.org/cgi-bin/niceprot.pl? A second agent, fremanezumab (Ajovy™), was approved in September 2018. The CALCRL gene encodes a G protein-coupled receptor (GPCR) that forms an active signaling complex for either adrenomedullin (ADM; 103275) or calcitonin gene-related peptide (CGRP; see 114130), depending on the receptor's interaction with RAMP proteins.Interaction of CALCRL with RAMP2 or RAMP3 leads to the formation of a receptor complex that binds ADM, whereas interaction with RAMP1 … The calcitonin receptor and other members of its family may complex to accessory proteins called receptor-activity-modifying proteins or RAMPs that change the cellular location or phenotype of the receptor. Interaction of CTR with calcitonin can inhibit multinucleation of TRAP+ mononucleated pre-osteoclasts without altering the RNA expression of RANK, Cfs1R, or a wide array of transcription factors and genes important for differentiation and activation, including the genes discussed above that have been suggested to have roles regulating osteoclast fusion [101]. The calcitonin receptor (CTR) is a GPCR [213] in the same group B subfamily that also includes the receptors for vasoactive intestinal peptide, secretin, and PTH and PTHrP [214]. CGRP and its receptors are distributed not only in the central and peripheral nervous system but also in the cardiovascular system, both in blood vessels and in the heart. In birds, fishes, and other nonmammalian vertebrates, calcitonin is secreted by cells of the glandular ultimobranchial bodies. This receptor is expressed during development and is involved in morphogenesis. Calcitonin is a is a peptide hormone secreted by the C-cells of the thyroid gland endogenously; calcitonin-salmon is a calcitonin receptor agonist. Lipton RB, Dodick DW, Ailani J, et al. Although generally less abundant than the hCT(a) receptor, this splice variant is significantly expressed in the ovary, placenta, bone marrow, and lung.
An evidence describes the source of an annotation, e.g. Evans blue was used to examine large molecule penetration into the rat TG. These subunits include: the CTR; the calcitonin receptor-like receptor (CLR), and three accessory proteins termed receptor activity-modifying proteins (RAMPs). Blockade of CGRP is a new therapeutic target for patients with migraine. Further discussion of calcitonin can be found in Chapter 75 (Civitelli). See identical proteins and their annotated locations for NP_031614.2. [9] It may also affect the ovaries in women and the testes in men. The regulatory portion of the CTR gene contains three putative promoters (P1, P2, and P3), giving rise to multiple CTR isoforms, which differ in the 5′ region of the gene and generate 5′-untranslated regions of very different lengths, in a tissue-specific manner.124 Promoters P1 and P2 are utilized in osteoclasts, brain, and kidney, and the proximal promoter of the human CTR (hCTRP1) was transcriptionally active in all cell lines tested, with high-level activity dependent on an 11 bp Sp1/Sp3 binding site.125 In contrast, promoter P3 appears to be osteoclast-specific and is sensitive to the osteoclast-inducing cytokine, RANKL, as well as the RANKL-induced transcription factor, NFATc1, consistent with a role for the latter in regulating the CTR gene in osteoclasts.126, The human CTR gene is located on chromosome 7 at 7q21.3. UniProtKB. The receptor signals through multiple pathways, including activation of adenylate cyclase, leading to inhibition of bone resorption. Endocrinology. UniParc. Subcellular location: Cell membrane: Synonyms: Calcitonin receptor; CT-R; C1A/C1B; Calcr: Background: This is a receptor for calcitonin. x; UniProtKB. Protein knowledgebase. The network of endoplasmic reticulum-resident chaperones (ERp72, GRP94, calreticulin, and BiP) interacts with apolipoprotein b regardless of its lipidation state", "Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly", "Calcitonin and calcitonin receptors: bone and beyond", "Cloning, characterization, and expression of a human calcitonin receptor from an ovarian carcinoma cell line", "An isoform of the human calcitonin receptor is expressed in TT cells and in medullary carcinoma of the thyroid", "Calcitonin receptor polymorphism is associated with a decreased fracture risk in post-menopausal women", "A novel calcitonin receptor gene in human osteoclasts from normal bone marrow", "Regulation of calcitonin receptor by glucocorticoid in human osteoclast-like cells prepared in vitro using receptor activator of nuclear factor-kappaB ligand and macrophage colony-stimulating factor", "C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells", "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences", https://en.wikipedia.org/w/index.php?title=Calcitonin_receptor&oldid=997621091, Creative Commons Attribution-ShareAlike License, This page was last edited on 1 January 2021, at 12:42. Lipton RB, Croop R, Stock EG, et al. The calcitonin receptor is thought to couple to the heterotrimeric guanosine triphosphate-binding protein that is sensitive to cholera toxin. Calcitonin is a hormone that the C-cells in the thyroid gland produce and release. CTR isoforms generated from alternative splicing have been described in a number of normal tissues and tumors. Elizabeth Holt, John J. Wysolmerski, in Vitamin D (Third Edition), 2011. The calcitonin receptor (CTR) is a GPCR [213] in the same group B subfamily that also includes the receptors for vasoactive intestinal peptide, secretin, and PTH and PTHrP [214]. It is interesting to note that the mouse CTR gene is expressed preferentially from the maternal allele in brain, with no allelic bias detected in other tissues, indicating that the mouse CTR gene is imprinted in a tissue-specific manner.127, HARRY C. BLAIR, ... MONE ZAIDI, in Osteoporosis (Third Edition), 2008. The calcitonin receptor is a seven‐transmembrane G‐protein coupled receptor which is located on osteoclasts, in kidney, and in brain. This is not a sign that the medication isn't working properly.. Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.. There are three RAMPS, all of which shift the calcitonin receptor to bind amylin or CGRP with higher affinity than calcitonin. The Ci-CT receptor (Ci-CTR) was cloned from the C. intestinalis central nervous system [1]; neither Xenopus oocytes nor mammalian culture cells express functional Ci-CTR [1]. The calcitonin receptor is encoded by the CALCR gene and comprises >90 kb and 14 exons. The CTR is coupled to multiple signal transduction pathways via Gs, Gq, and Gi to adenylyl cyclase-cAMP-PKA, MAP kinases, and phospholipases A2, C, and D generating increased cytosolic Ca+2 and PKC activation, which contribute to different responses (reviewed in [100]). Copyright © 2021 Elsevier B.V. or its licensors or contributors. Calcitonin is secreted by by the parafollicular cells (also referred to as calcitonin cells or C cells) of the thyroid and other neuroendocrine cells. Girgis, ... L. Mancini, in Encyclopedia of Biological Chemistry (Second Edition), 2013. The mechanism for this analgesic response is believed to be dependent on central nervous system receptors. Currently, there are several anti-CGRP treatments undergoing clinical trials. Calcitonin gene-related peptide and adrenomedullin exert potent effects in skin but their cellular targets are unknown. Calcitonin receptor activation leads to a rise in cAMP/PKA and PKC activity. It belongs to G-protein-coupled receptors (GPCRs). Their receptors consist of one of two GPCRs, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CLR). [102] have shown that the normal loss of bone mineral density that occurs during lactation is increased in CT/CGRP KO mice compared to littermate controls and this is normalized by administration of salmon CT to the CT/CRGP KO mice. Association with RAMP1 creates a receptor that recognizes amylin and CGRP with relatively equal affinities, whereas association with RAMP2 or RAMP3 generates receptors that have higher affinity for amylin [215,216]. Like other family members, it contains seven hydrophobic helices that anchor it in the plasma membrane. However, in management of bone loss with bone pain, a trial of calcitonin is justified because many patients find rapid and significant relief, despite the limited effect on bone loss [108]. Calcitonin receptor (CTR) is a member of a subfamily of the seven-transmembrane domain G protein-coupled receptor superfamily that includes several peptide receptors. The calcitonin receptor is a GPCR [161] in the same group B sub-family that also includes the receptors for vasoactive intestinal peptide, secretin, and PTH and PTHrP [162]. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase. Medicines that interact with calcitonin may either decrease its effect, affect how long it … Subsequent cloning of the gene demonstrated that it is approximately 70 kb in length and contains at least 14 exons, 12 of which encode porcine CTR [6]. The Calcitonin Receptor inhibits bone resorption. However, it is not a marker for avian osteoclasts, as they do not express it. The binding of CT to its receptor results in the activation of either adenylate cyclase or phospholipase C. CT receptors are highly expressed in osteoclasts, in the kidney and in the hypothalamus in areas involved with pain, perception, and appetite. Status: VALIDATED The receptor signals through multiple pathways, including activation of adenylate cyclase, leading to inhibition of bone resorption. NM_001042725NM_007588NM_001355192NM_001377018, NP_001036190NP_031614NP_001342121NP_001363947, The calcitonin receptor (CT) is a G protein-coupled receptor that binds the peptide hormone calcitonin and is involved in maintenance of calcium homeostasis,[5] particularly with respect to bone formation and metabolism.[6][7][8]. Some of these treatments involve monoclonal antibodies, which reduce the activity of CGRP, potentially leading to fewer migraine attacks. Calcitonin acts primarily on bone, but direct renal effects and actions on the gastrointestinal tract are also recognized. Interactions. The first calcitonin receptor (CTR) was cloned in 199. results show the presence of calcitonin receptor-like receptor and receptor activity-modifying proteins in middle meningeal, middle cerebral, pial, and superficial temporal vessels. You may have increased bone pain during the first few months of treatment with calcitonin injection. It binds with high affinity and responds to CT. Hoshiya et al. Calcitonin also rapidly induces loss of the ruffled border, quiescence, and cell retraction of mature activated osteoclasts resulting in inhibition of bone resorption both in vivo and in vitro. The large (~600 amino acids) extracellular domain is known to be critical to interactions with extracellular calcium. There are several splice variants of the calcitonin receptor (CT) in several different species. However, global deletion of the cytoplasmic C-terminus of CTR using a Cre/loxP system showed that CTR has a modest physiological role in the regulation of bone and calcium homeostasis in the basal state in mice, which was accentuated after 1,25(OH)2D3-induced hypercalcemia. The function of the CT receptor protein is modified through its interaction with Receptor activity-modifying proteins (RAMPs), forming the multimeric amylin receptors AMY1 (CT + RAMP1), AMY2 (CT + RAMP2), and AMY3 (CT+ RAMP3). No gene encoding a receptor activity-modifying protein (RAMP), which is a prerequisite for ligand selectivity and endoplasmic reticulum–plasma membrane translocation of some receptors in vertebrates, has been detected in the C. intestinalis genome [1]. We use cookies to help provide and enhance our service and tailor content and ads. CTR has roles in a diverse range of physiological functions and is relevant to three distinct hormonal systems: amylin, calcitonin (CT), and calcitonin gene-related peptide (CGRP). The calcium-sensing receptor is a member of the G protein-coupled receptor family. CTR exists as several different isoforms resulting from alternative splicing of a single gene that are different in different species [99]. Numerous studies have demonstrated that it is a specific marker of osteoclast differentiation and the degree of surface expression increases as osteoclasts undergo fusion and activation. The association of CLR with RAMP2 or 3 results in AM receptors. The calcitonin receptor is a seven‐transmembrane G‐protein coupled receptor which is located on osteoclasts, in kidney, and in brain. The calcitonin receptor (CTR) is a seven-transmembrane class II G-protein-coupled receptor for the 32-amino-acid calcitonin, and is highly expressed on the osteoclast plasma membrane. This supports the concept that CTR plays an important role in protecting the skeleton in times of calcium stress such as induced hypercalcemia, pregnancy, lactation, and in states of high bone turnover. By continuing you agree to the use of cookies. The best characterized, and most common, of these is the hCT(b) (formerly hCTR1 or CTRI1+) receptor as recently defined in IUPHAR guidelines Poyner et al (2002). Calcitonin is formed by the proteolytic bosom of a larger prepropeptide, which is the product of the CALC1 genetics (CALCA). J:22084 Yamin M, et al., Cloning and characterization of a mouse brain calcitonin receptor complementary deoxyribonucleic acid and mapping of the calcitonin receptor gene. In the case of the calcitonin receptor, the association with a RAMP results in the creation of the receptor for amylin [162]. It is coupled by Gs to adenylate cyclase, and thereby to the generation of cAMP in target cells. Immunofluorescence was used to study the detailed distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) in whole-mount rat dura mater and in human dural vessels. Q60755;%20RefSeq%20NP_031614, http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db= protein&list_uids=6680830&dopt= GenPept, Encyclopedia of Biological Chemistry (Second Edition), Parathyroid Hormone, Parathyroid Hormone–Related Protein, and Calcitonin, Endocrinology: Adult and Pediatric (Seventh Edition). David M. Findlay, ... T. John Martin, in Endocrinology: Adult and Pediatric (Seventh Edition), 2016. Members of the calcitonin family of peptides bind to transmembrane-bound, G-protein-coupled receptors (GPCRs), commonly referred to as the calcitonin family of receptors. The predicted structure of the mefugu fish CTR gene is more complex than the human gene, with an additional nine exons.113 It is interesting to note that both fish and mammalian genes code for micro-RNA (miR)-489 in intron 3, the function of which remains to be determined. Invertebrate CTR (AB485673) has also been sequenced from the protochordate Ciona intestinalis. 2019;381(2):142-149. Calcitonin receptor isoforms generated from alternative splicing have been described in a number of normal tissues and tumors. Some of these isoforms are nonfunctional and may have a regulatory effect by inhibiting calcitonin signaling [215]. In fish, calcitonin is a potent antagonist of osteoclastic activity, but it has proven to be of limited activity in humans. The calcitonin receptor is thought to couple to the heterotrimeric guanosine triphosphate-binding protein that is sensitive to cholera toxin. Malignant tumors arising from thyroid C cells (medullary thyroid carcinoma) usually produce elevated levels of calcitonin. These pig and mouse chromosomal regions are homologous to 7q in humans. How does calcitonin work? Calcitonin receptors are present on osteoclasts and in the central nervous system. Porcine CTR cDNA was obtained for the first time in 1991.
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