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A galanin receptor subtype 1 specific agonist
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
Stockholm University, Faculty of Science, Department of Neurochemistry and Neurotoxicology.
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2005 (English)In: International Journal of Peptide Research and Therapeutics, ISSN 1573-3904, Vol. 11, no 1, 17-27 p.Article in journal (Refereed) Published
Abstract [en]

The chimeric peptide M617, galanin(1–13)-Gln14-bradykinin(2–9)amide, is a novel galanin receptor ligand with increased subtype specificity for GalR1 and agonistic activity in cultured cells as well as in vivo. Displacement studies on cell membranes expressing hGalR1 or hGalR2 show the presence of a high affinity binding site for M617 on GalR1 (K i=0.23±.12 nM) while lower affinity was seen towards GalR2 (K i=5.71±1.28 nM) resulting in 25-fold specificity for GalR1. Activation of GalR1 upon stimulation with M617 is further confirmed by internalization of a GalR1-EGFP conjugate. Intracellular signaling studies show the ability of M617 to inhibit forskolin stimulated cAMP formation with 57% and to produce a 5-fold increase in inositol phosphate (IP) accumulation. Agonistic effects on signal transduction are shown on both receptors studied after treatment with M617 in the presence of galanin. In noradrenergic locus coeruleus neurons, M617 induces an outward current even in the presence of TTX plus Ca2+, high Mg2+, suggesting a postsynaptic effect. Intracerebroventricular (i.c.v.) administration of M617 dose-dependently stimulates food uptake in rats while, in contrast, M35 completely fails to affect the feeding behavior. Spinal cord flexor reflex is facilitated by intrathecal (i.t.) administration of M617 as well as galanin with no significant change upon pre-treatment with M617. M617 dose dependently antagonizes the spinal cord hyperexcitablility induced by C-fiber conditioning stimulus and does neither enhance nor antagonize the effect of galanin. These data demonstrate a novel galanin receptor ligand with subtype specificity for GalR1 and agonistic activity, both in vitro and in vivo.

Place, publisher, year, edition, pages
2005. Vol. 11, no 1, 17-27 p.
Keyword [en]
cAMP production, chimeric peptide, feeding behavior, galanin, galanin receptor, inositol phosphate production, locus coeruleus, nociception, receptor internalization, receptor specificity
National Category
Biological Sciences Chemical Sciences
Identifiers
URN: urn:nbn:se:su:diva-23018DOI: 10.1007/s10989-004-1717-zOAI: oai:DiVA.org:su-23018DiVA: diva2:189918
Available from: 2007-01-03 Created: 2007-01-03 Last updated: 2015-04-21Bibliographically approved
In thesis
1. Subtype selective activation and molecular characterization of galanin receptors
Open this publication in new window or tab >>Subtype selective activation and molecular characterization of galanin receptors
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Showing an extensive distribution in the nervous system, and often in co-localization with the classical neurotransmitters, neuropeptides are functioning as important modulators of neuronal signaling. Subsequently, compelling evidence has implicated a modulatory role for the neuropeptide galanin in several physiological functions. The effect of galanin is trancduced intracellularly by three different receptors, and defining the explicit effect from these receptor subtypes is of outmost interest, and likely to result in future therapeutic utilization of the galanin system.

The main aim of this thesis was to improve the development of subtype selective ligands utilized to differentiate between the galanin receptor subtypes. To achieve this, we have designed and developed novel galanin receptor ligands and characterized the molecular interactions necessary for ligand bindig at the GalR2 subtype.

The major findings include the introduction and characterization of two galanin receptor ligands, selectively activating GalR1 or inhibiting GalR2. Although having moderate selectivity, the two ligands have been utilized in a number of studies, pursuing their initial presentation, in order to differentiate between the galanin receptors and to establish their specific function. Further optimization is likely to improve the selectivity and utilization of these ligands. By identifying the major pharmacophores in the Gal(2-11) ligand and the residues in the GalR2 subtype participating in ligand binding, we have been able to characterize the binding site in this receptor subtype and interactions that are of significance for recognition of subtype specific ligands. Together, these findings on GalR2 and Gal(2-11) are of importance for future design of ligands acting on this receptor.

Place, publisher, year, edition, pages
Stockholm: Institutionen för neurokemi, 2007. 87 p.
National Category
Neurosciences
Identifiers
urn:nbn:se:su:diva-1344 (URN)91-7155-325-8 (ISBN)
Public defence
2007-02-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 13:00 (English)
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Available from: 2007-01-03 Created: 2007-01-03 Last updated: 2010-02-24Bibliographically approved

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