title: Multiple interaction sites of galnon trigger its biological effects.
abstract: Galnon was first reported as a low molecular weight non-peptide agonist at galanin receptors [Saar et al. (2002) Proc. Natl. Acad. Sci. USA 99, 7136-7141]. Following its systemic administration, this synthetic ligand affected a range of important physiological processes including appetite, seizures and pain. Physiological activity of galnon could not be explained solely by the activation of the three known galanin receptors, GalR1, GalR2 and GalR3. Consequently, it was possible that galnon generates its manifold effects by interacting with other signaling pathway components, in addition to via GalR1-3. In this report, we establish that galnon: (i) can penetrate across the plasma membrane of cells, (ii) can activate intracellular G-proteins directly independent of receptor activation thereby triggering downstream signaling, (iii) demonstrates selectivity for different G-proteins, and (iiii) is a ligand to other G-protein coupled receptors (GPCRs) in addition to via GalR1-3. We conclude that galnon has multiple sites of interaction within the GPCR signaling cascade which mediate its physiological effects.
authors.affiliation: Department of Neurochemistry, Stockholm University, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Florén
authors.forename: Ulla
authors.initials: U
authors.lastname: Sollenberg
authors.forename: Linda
authors.initials: L
authors.lastname: Lundström
authors.forename: Matjaz
authors.initials: M
authors.lastname: Zorko
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.forename: Metka
authors.initials: M
authors.lastname: Budihna
authors.forename: Mark
authors.initials: M
authors.lastname: Wheatley
authors.forename: Negin P
authors.initials: NP
authors.lastname: Martin
authors.forename: Kalle
authors.initials: K
authors.lastname: Kilk
authors.forename: Andrey
authors.initials: A
authors.lastname: Mazarati
authors.forename: Tamas
authors.initials: T
authors.lastname: Bartfai
authors.forename: Maria
authors.initials: M
authors.lastname: Lindgren
authors.forename: Ulo
authors.initials: U
authors.lastname: Langel
mesh_terms: D000818:Animals; D002460:Cell Line; D003331:Coronary Vessels / Q000378:metabolism; D003374:Coumarins / Q000737:chemistry / Q000378:metabolism*; D006224:Cricetinae; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D037342:Pertussis Toxin / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D044088:Receptors, Galanin / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine
chemical_list: C456547:7-((9-fluorenylmethoxycarbonyl)cyclohexylalanyllysyl)amino-4-methylcoumarin; D003374:Coumarins; D008024:Ligands; D020033:Protein Isoforms; D044088:Receptors, Galanin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D037342:Pertussis Toxin; D019204:GTP-Binding Proteins