Fischer
Fakultäten » Medizinische Fakultät » Universitätsklinik Balgrist und Schweizerisches Paraplegikerzentrum » Orthopädie » Prof. Dr. Jan Fischer (ausgetreten) » Fischer
Completed research project
| Title / Titel | Molecular interactions of G protein-coupled receptors of the calcitonin family with receptor activity modifying proteins (RAMP) | ||||||
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| Abstract (PDF, 14 KB) | |||||||
| Original title / Originaltitel | Molecular interactions of G protein-coupled receptors of the calcitonin family by receptor activity modifying proteins (RAMP) | ||||||
| Summary / Zusammenfassung | The aims of the Research Laboratory for Calcium Metabolism of the University of Zurich focus on the role in normal physiology and disease of parathyroid hormone and parathyroid hormone-related protein and of the calcitonin peptide family which includes the neuropeptide calcitonin gene-related peptide (CGRP) and adrenomedullin, both with potent cardiovascular activities, and amylin as a predominant component in amyloid fibrils in islets of patients with diabetes type II. Present research projects concentrate on cloning and functional analysis of receptors for these peptides. This involves studies on ligand/receptor interactions and intracellular signaling, receptor-mediated regulation of reporter genes and localization studies with in situ hybridization and immunohistochemistry. In addition biologically relevant effects of the peptides include regulation of cell growth, differentiation and apoptosis. Recent progress The identification of three novel receptor-activity-modifying proteins (RAMP) revealed a new functional principle of G protein-coupled receptors with seven transmembrane-domains. Calcitonin receptors (CTR) and calcitonin receptorlike receptors (CLR) of the B family of these receptors use RAMP as accessory proteins at the cell surface to modulate the specificity for the peptides of the calcitonin family such as of calcitonin generelated peptide (CGRP), adrenomedullin and amylin. The CTR/RAMP1 and the CLR/RAMP1 complexes are CGRP/amylin- and CGRP-receptors, respectively, distinguished by calcitonin and CGRP antagonists. Another amylin receptor isotype is revealed in cells coexpressing CTR and RAMP3. RAMP2 and -3 associate with the CLR defining adrenomedullin receptors. Thus, the CTR and the CLR individually interact with the three RAMP at the cell surface to form high affinity receptors for the four peptides of the calcitonin family. Differential actions of CGRP and adrenomedullin in the pulmonary and cardiovascular systems are studied in transgenic animals that overexpress corresponding receptors and mutants thereoff. Overexpression of the CLR in transgenic mice under control of a smooth muscle alpha-actin promoter revealed a glaucoma-like phenotype and skeletal defects. Weitere Informationen |
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| Publications / Publikationen | Husmann, K., Born, W., Fischer, J.A., Muff, R.: Three receptor-activity-modifying proteins define calcitonin gene-related peptide or adrenomedullin selectivity of the mouse calcitonin-like receptor in COS-7 cells.. Biochem. Pharmacol. 66: 2107-2115 (2003). Steiner, S., Born, W., Fischer, J.A., Muff, R.: The function of conserved cysteine residues in the extracellular domain of human receptor-activity-modifying protein 1. FEBS Lett. 555: 285-290 (2003).Koller, D., Ittner, L.M., Muff, R., Husmann, K., Fischer, J.A., Born, W.: Selective inactivation of adrenomedullin over calcitonin gene-related peptide receptor function by the deletion of amino acids 14 to 20 of the mouse calcitonin-like receptor. J. Biol. Chem. 279: 20387-20391 (2004) Ittner, L.M., Lüssi, F., Koller, D., Born, W., Fischer, J.A., Muff, R.: The aspartate69 residue of the calcitonin-like receptor is required for its functional expression together with receptor activity modifying proteins 1 and -2. Biochem. Biophys. Res. Commun. 319: 1203-1209 (2004)Poyner, D.R., Sexton, P.M., Marshall, I., Smith, D.M., Quirion, R., Born, W., Muff, R., Fischer, J.A., Foord, S.M.: International union of pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin and calcitonin receptors. Pharmacol. Reviews 54: 233-246 (2002). Muff, R., Born, W., Lutz, T., Fischer, J.A.: Biological importance of the peptides of the calcitonin family as revealed by disruption and transfer of corresponding genes. Peptides 25: 2027-2038 (2004)Weitere Informationen |
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| Keywords / Suchbegriffe | Adrenomedullin, Calcitonin Gene-Related Peptide (CGRP), Calcitonin Receptor Isotypes, Receptor Activity Modifying Proteins (RAMP) | ||||||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Universität Zürich (position pursuing an academic career), Others |
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| Duration of Project / Projektdauer | Sep 1997 to Jul 2005 |