Born
Fakultäten » Medizinische Fakultät » Universitätsklinik Balgrist und Schweizerisches Paraplegikerzentrum » Orthopädie » Prof. Dr. Walter Born » Born
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) | |||||
| Summary / Zusammenfassung | Research Projects Research on 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, is carried out in the laboratory of Prof. Dr. J. Vogel at the Institute of Veterinary Physiology of the University of Zurich. Present research projects concentrate on the biological relevance of the calcitonin receptor-like receptor (CLR) in interaction with receptor-activity-modifying proteins (RAMP) in transgenic mice overexpressing respective proteins. 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 receptor-like receptors (CLR) of the B family of G protein-coupled receptors with seven transmembrane domains use RAMP as accessory proteins at the cell surface to modulate the specificity for the peptides of the calcitonin family such as of calcitonin gene-related 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. Recent work demonstrated that the overexpression of the CLR in the pupillary sphincter muscle of mice causes adrenomedullin receptor-mediated chronic relaxation and, as a consequence, a phenotype reflecting human acute angle closure glaucoma. In a second study, these mice presented enhanced and sustained tachycardia in response to iv injections of CGRP mediated by sympathetic activity. |
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| Publications / Publikationen | 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)Ittner, L.M., Koller, D., Muff, R., Fischer, J.A., Born, W. The residues 23 to 60 of the calcitonin receptor-like receptor in chimeras with the parathyroid hormone receptor associate with receptor-activity-modifying protein 1. Biochemistry: 44: 5749-5754 (2005)Wurdak, H., Ittner, L.M., Lang, K.S., Leeven, P., Suter, U., Fischer, J.A., Karlsson, S., Born, W., Sommer, L.: DiGeorge syndrome caused by inactivation of TGF signalling in neural crest stem cells. Genes and Development: 19: 530-535 (2005).Dumont, C.E., Born, W.: Stimulation of neurite outgrowth in a human nerve scaffold designed for peripheral nerve reconstruction. J. Biomed. Material Res. Part B: Appl. Biomater. 73B: 194-202 (2005).Ittner, L.M., Wurdak, H., Schwerdtfeger, K., Kunz, T., Leveen, P., Hjalt, T.A., Suter, U., Karlsson, S., Remé, C., Born, W., Sommer, L.: Compound developmental eye disorders upon TGF signal inactivation in neural crest stem cells. J. Biol. 4: 11.1-11.16 (2005).Tam, C.W., Husmann, K., Clark, N.C., Clark, J.E., Lazar, Z., Ittner, L.M., Götz, J., Douglas, G., Grant, A.D., Sugden, D., Poston, L., Poston, R., McFadzean, I., Marber, M.S., Fischer, J.A., Born, W., Brain, S.: Enhanced vascular responses to adrenomedullin in mice overexpressing receptor-activity-modifying protein 2. Circulation Res. 98: 262-270 (2006)Ittner, L.M., Schwerdtfeger, K., Kunz, T., Muff, R., Husmann, K., Reme, C., Grimm, C., Hafezi, F., Lang, K.S., Kurrer, M.O., Götz, J., Born, W., Fischer, J.A.: Transgenic mice with ocular overexpression of an adrenomedullin receptor reflect human acute angle-closure glaucoma. Clinical Science 114: 49-58 (2008), published online 30. 11. 2007Kunz, T., Mueller-Steiner, S., Schwerdtfeger, K., Kleinert, P., Troxler, H., Kelm, J.M., Ittner, L.M., Fischer, J.A., Born, W.: Interaction of receptor-activity-modifying protein1 with tubulin. BBA-General Subjects 1770: 1145-1150 (2007)Kunz, T. H., Scott, M., Ittner, L.M., Fischer, J.A., Born, W., Vogel, J.: Calcitonin gene-related peptide-evoked sustained tachycardia in calcitonin receptor-like receptor transgenic mice is mediated by sympathetic activity. Am. J. Physiol. Heart Circ. Physiol. 293: H2155-H2160 (2007), published online July 27, (2007) | ||||
| 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), SNF (Personen- und Projektförderung), Foundation |
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| In collaboration with / In Zusammenarbeit mit |
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| Duration of Project / Projektdauer | Apr 2003 to Nov 2008 |