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A novel GalR2-specific peptide agonist
Stockholm University, Faculty of Science, Department of Neurochemistry.
Stockholm University, Faculty of Science, Department of Neurochemistry. University of Tartu, Estonia.
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2009 (English)In: Neuropeptides, ISSN 0143-4179, E-ISSN 1532-2785, Vol. 43, no 3, 187-192 p.Article in journal (Refereed) Published
Abstract [en]

The galanin peptide family and its three receptors have with compelling evidence been implicated in several high-order physiological disorders. The co-localization with other neuromodulators and the distinct up-regulation during and after pathological disturbances has drawn attention to this neuropeptide family. In the current study we present data on receptor binding and functional response for a novel galanin receptor type 2 (GalR2) selective chimeric peptide, M1145 [(RG)(2)-N-galanin(2-13)-VL-(P)(3)-(AL)(2)-A-amide]. The M1145 peptide shows more than 90-fold higher affinity for GalR2 over GalR1 and a 76-fold higher affinity over GalR3. Furthermore, the peptide yields an agonistic effect in vitro, seen as an increase in inositol phosphate (IP) accumulation, both in the absence or the presence of galanin. The peptide design with a N-terminal extension of galanin(2-13), prevails new insights in the assembly of novel subtype specific ligands for the galanin receptor family and opens new possibilities to apply the galanin system as a putative drug target.

Place, publisher, year, edition, pages
2009. Vol. 43, no 3, 187-192 p.
Keyword [en]
Galanin, GALP, GPCR, Agonist, GalR, Chimeric peptide, Inositol phosphate production, Receptor specificity
National Category
Neurosciences Biochemistry and Molecular Biology
Research subject
Neurochemistry with Molecular Neurobiology
URN: urn:nbn:se:su:diva-36269DOI: 10.1016/j.npep.2009.04.004ISI: 000267403000002PubMedID: 19467704OAI: diva2:387004
Available from: 2011-01-13 Created: 2010-01-22 Last updated: 2015-04-21Bibliographically approved
In thesis
1. Delineating Ligand-Receptor Interactions and the Design of Subtype Selective Galanin Receptor Ligands
Open this publication in new window or tab >>Delineating Ligand-Receptor Interactions and the Design of Subtype Selective Galanin Receptor Ligands
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

We now celebrate that it is 30 years since galanin was first isolated. During these three decades galanin has been identified in numerous tissues and physiological processes, and in an abundant number of species. In the nervous system galanin primarily displays a modulatory role. The galaninergic system consists of a number of bioactive peptides with a highlyplastic expression pattern and three different receptors, GalR1-GalR3. The lack of receptor subtype selective ligands and antibodies have severely hampered the characterization of this system. Therefore, most of the knowledgehas been drawn from experiments with transgenic animals, which has givensome major conclusions, despite the risk of inducing compensatory effects inthese animal studies. Therefore, the production of subtype selective ligandsis 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, especially the development of novel galanin receptor subtype selective ligands. Paper I demonstrates the potential to N-terminally extend galanin analogues and the successful development of a GalR2 selective ligand. In addition, a cell line stably expressing GalR3 was developed to improve and simplify future evaluations of receptor subtype selective galanin ligands. Paper II extends the number of GalR2 selective ligands and shows that i.c.v. administration of galanin receptor ligands stimulates food intake through GalR1. Paper III demonstrates the successful development of a mixed GalR1/GalR2 agonist without any detectable interaction with GalR3. Subsequently, this peptide was used to delineate which receptor subtype mediatesthe neuroprotective effects of galanin in the CA3 region of hippocampus. Furthermore, a robust protocol for detection of receptor activation was developed to ease the detection of the relative potency of novel ligands at the three galanin receptor subtypes. Paper IV describes the finding of several essential amino acids for ligand interaction in GalR3 through the performance of an L-alanine mutagenesis study. A constructed in silico homology model of GalR3 confirmed and extended these findings. In conclusion, this thesis provides a novel design strategy for galanin receptor ligands and increases the understanding of ligand interactions with the GalR3. Furthermore, published ligands together with new galanin analogues have proven to be highly receptor specific, thus implicating that a future delineation of the galaninergic system as a therapeutic target is possible.

Place, publisher, year, edition, pages
Stockholm: Department of Neurochemistry, Stockholm University, 2012. 96 p.
National Category
Natural Sciences
Research subject
Neurochemistry with Molecular Neurobiology
urn:nbn:se:su:diva-75503 (URN)978-91-7447-503-6 (ISBN)
Public defence
2012-06-01, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrheniusväg 16 B, Stockholm, 13:00 (English)
At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.Available from: 2012-05-10 Created: 2012-04-20 Last updated: 2015-04-21Bibliographically approved

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