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Preferential activation by galanin 1-15 fragment of the GalR1 protomer of a GalR1-GalR2 heteroreceptor complex
- Source :
- Recercat. Dipósit de la Recerca de Catalunya, Universitat Jaume I, UPCommons. Portal del coneixement obert de la UPC, Universitat Politècnica de Catalunya (UPC)
- Publication Year :
- 2014
-
Abstract
- The three cloned galanin receptors show a higher affinity for galanin than for galanin N-terminal fragments. Galanin fragment (1-15) binding sites were discovered in the rat Central Nervous System, especially in dorsal hippocampus, indicating a relevant role of galanin fragments in central galanin communication. The hypothesis was introduced that these N-terminal galanin fragment preferring sites are formed through the formation of GalR1-GalR2 heteromers which may play a significant role in mediating galanin fragment (1-15) signaling. In HEK293T cells evidence for the existence of GalR1-GalR2 heteroreceptor complexes were obtained with proximity ligation and BRET2 assays. PLA positive blobs representing GalR1-GalR2 heteroreceptor complexes were also observed in the raphe-hippocampal system. In CRE luciferase reporter gene assays, galanin (1-15) was more potent than galanin (1-29) in inhibiting the forskolin-induced increase of luciferase activity in GalR1-GalR2 transfected cells. The inhibition of CREB by 50 nM of galanin (1-15) and of galanin (1-29) was fully counteracted by the non-selective galanin antagonist M35 and the selective GalR2 antagonist M871. These results suggested that the orthosteric agonist binding site of GalR1 protomer may have an increased affinity for the galanin (115) vs galanin (1-29) which can lead to its demonstrated increase in potency to inhibit CREB vs galanin (1-29). In contrast, in NFAT reporter gene assays galanin (1-29) shows a higher efficacy than galanin (115) in increasing Gq/11 mediated signaling over the GalR2 of these heteroreceptor complexes. This disbalance in the signaling of the GalR1-GalR2 heteroreceptor complexes induced by galanin (1-15) may contribute to depression-like actions since GalR1 agonists produce such effects. (C) 2014 Elsevier Inc. All rights reserved.
- Subjects :
- 3RD intracellular loop
Galanin receptor
Galanin -- Receptors
Hippocampus
Biochemistry
In situ Proximity Ligation Assay
Allosteric receptor-receptor interactions
Ventral limbix cortex
Genes, Reporter
Promoter Regions, Genetic
Receptor
N-terminal galanin fragment
Neurons
Subtypes
Brain Mapping
biology
digestive, oral, and skin physiology
NFAT
CREB-Binding Protein
Rat-brain
GalR1-GalR2 heteromers
Proteïnes -- Receptors
hormones, hormone substitutes, and hormone antagonists
Signal Transduction
Agonist
endocrine system
medicine.drug_class
Ciències de la salut::Medicina [Àrees temàtiques de la UPC]
Green Fluorescent Proteins
Biophysics
Galanin
Bradykinin
CREB
Heteroreceptor
Receptor-receptor interactions
Allosteric Regulation
medicine
Animals
Humans
Binding site
Proteins -- Receptors
Molecular Biology
Galanina -- Receptors
Galactolipids
Cell Biology
Binding
Molecular biology
Peptide Fragments
Receptor, Galanin, Type 1
Rats
Receptor, Galanin, Type 2
HEK293 Cells
Gene Expression Regulation
nervous system
biology.protein
Protein Multimerization
Heteroreceptor complexes
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Recercat. Dipósit de la Recerca de Catalunya, Universitat Jaume I, UPCommons. Portal del coneixement obert de la UPC, Universitat Politècnica de Catalunya (UPC)
- Accession number :
- edsair.doi.dedup.....6cd64463ff7c4ed04c5b063ac583e5af