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Galanin receptor ligands
Stockholm University, Faculty of Science, Department of Neurochemistry. (Ülo Langel)
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

In the nervous system galanin primarily displays a modulatory role. The galaninergic system consists of a number of bioactive peptides with a highly plastic expression pattern and three different receptors. The lack of receptor subtype selective ligands and antibodies have severely hampered the charac-terization of this system. Therefore, most of the knowledge has been drawn from experiments with transgenic animals, which has given some major conclusions, despite the compensatory effects seen in several animal studies. Therefore, the production of subtype selective ligands is of great importance to delineate the galanin system and slowly experimental data from receptor subtype selective ligand trials is emerging.

This thesis aims at studying galanin receptor-ligand interactions and to increase and improve the utilized tools in the galanin research field, espe-cially the development of novel galanin receptor subtype selective ligands. Paper I demonstrates the potential to N-terminally extend galanin ana-logues and the successful development of a galanin receptor 2 (GalR2) selec-tive ligand. In addition, a cell line stably expressing galanin receptor 3 (GalR3) was developed, to improve and simplify future evaluations of sub-type selective galanin ligands. Paper II measures the affinities of M617 and M871 to GalR3 and demon-strates that M871 preferentially binds GalR2. Furthermore, the relatively high affinity of M617 was evaluated by assessing the contribution in recep-tor interaction of individual amino acid residues in the C-terminal part of the M617.

In conclusion, this thesis has provided a novel design strategy for galanin receptor ligands and increased the understanding of ligand interactions with the GalR3. Furthermore, M1145 has together with new analogues proven to be highly GalR2 specific, holding promises to future delineation of the galaninergic system as a therapeutic target.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University , 2009. , 50 p.
Keyword [en]
Galanin, GALP, GPCR, Agonist, GalR, Chimeric peptide, Inositol phosphate production, Receptor specificity
National Category
Natural Sciences
Research subject
Neurochemistry and Molecular Neurobiology
Identifiers
URN: urn:nbn:se:su:diva-59743ISBN: 978-91-7155-915-9 (print)OAI: oai:DiVA.org:su-59743DiVA: diva2:430469
Presentation
2009-09-11, Heilbronnsalen, Institutionen för neurokemi, Svante Arrhenius väg 21A, Stockholm, 12:15 (English)
Opponent
Supervisors
Available from: 2011-11-03 Created: 2011-07-11 Last updated: 2015-04-21Bibliographically approved
List of papers
1.
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2. Binding of Chimeric Peptides M617 and M871 to Galanin Receptor Type 3 Reveals Characteristics of Galanin Receptor–Ligand Interaction
Open this publication in new window or tab >>Binding of Chimeric Peptides M617 and M871 to Galanin Receptor Type 3 Reveals Characteristics of Galanin Receptor–Ligand Interaction
2010 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3149, Vol. 16, no 1, 17-22 p.Article in journal (Refereed) Published
Abstract [en]

The neuropeptide galanin is ascribed to a variety of biological effects, but selective compounds to examine the specific roles of the three receptor subtypes are currently lacking. The recently introduced chimeric peptide ligands M617 and M871 target the galanin receptors GalR1 and GalR2, respectively. These peptides have been used to examine receptor function in vitro and in vivo, but their affinity to GalR3 has not been tested. Here, we report the binding affinity of these peptides at human GalR3 and demonstrate that M617 binds GalR3 and stimulates this receptor in an agonistic manner, whereas M871 shows very low affinity towards GalR3 (Ki 49.2 ± 9.4 nM and > 10 microM respectively). An L-alanine scan of M617 revealed the importance of the ligand C-terminus in GalR3 binding, which stands in contrast to the structural requirements for binding to GalR1 and GalR2. These data provide insights into galanin receptor ligand binding that should be considered when using these compounds in functional studies.

National Category
Neurosciences
Identifiers
urn:nbn:se:su:diva-37229 (URN)10.1007/s10989-009-9197-9 (DOI)000275791700003 ()
Available from: 2010-02-17 Created: 2010-02-17 Last updated: 2015-04-22Bibliographically approved

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