title: Dynamic modulation of FGFR1-5-HT1A heteroreceptor complexes. Agonist treatment enhances participation of FGFR1 and 5-HT1A homodimers and recruitment of β-arrestin2.
abstract: New findings show that neurotrophic and antidepressant effects of 5-HT in brain can, in part, be mediated by activation of the 5-HT1A receptor protomer in the hippocampal and raphe FGFR1-5-HT1A heteroreceptor complexes enhancing the FGFR1 signaling. The dynamic agonist modulation of the FGFR1-5-HT1A heteroreceptor complexes and their recruitment of β-arrestin is now determined in cellular models with focus on its impact on 5-HT1AR and FGFR1 homodimerization in the heteroreceptor complexes based on BRET(2) assays. The findings show that coagonist treatment with 8-OH-DPAT and FGF2 but not treatment with the 5-HT1A agonist alone markedly increases the BRETmax values and significantly reduces the BRET50 values of 5HT1A homodimerization. The effects of FGF2 or FGF20 with or without the 5-HT1A agonist were also studied on the FGFR1 homodimerization of the heteroreceptor complexes. FGF2 produced a marked and rapid increase in FGFR1 homodimerization which partially declined over a 10min period. Cotreatment with FGF2 and 5-HT1A agonist blocked this decline in FGFR1 homodimerization. Furthermore, FGF2 alone produced a small increase in the BRET(2) signal from the 5-HT1A-β-arrestin2 receptor-protein complex which was additive to the marked effect of 8-OH-DPAT alone. Taken together, the participation of 5-HT1A and FGFR1 homodimers and recruitment of β-arrestin2 was demonstrated in the FGFR1-5-HT1A heteroreceptor complexes upon agonist treatments.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. Electronic address: Dasiel.Borroto-Escuela@ki.se.
authors.forename: Dasiel O
authors.initials: DO
authors.lastname: Borroto-Escuela
authors.forename: Fidel
authors.initials: F
authors.lastname: Corrales
authors.forename: Manuel
authors.initials: M
authors.lastname: Narvaez
authors.forename: Julia
authors.initials: J
authors.lastname: Oflijan
authors.forename: Luigi F
authors.initials: LF
authors.lastname: Agnati
authors.forename: Miklós
authors.initials: M
authors.lastname: Palkovits
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D011487:Protein Conformation; D055503:Protein Multimerization; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D000071557:beta-Arrestins; D016222:Fibroblast Growth Factor 2; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Allosteric modulation; Bioluminescence resonance energy transfer; Fibroblast growth factor receptor 1; G-protein-coupled receptors; Heterocomplex; Homodimerization; Protein–protein interactions; Receptor tyrosine kinases; Serotonin receptors