Dynamic modulation of FGFR1-5-HT1A heteroreceptor complexes. Agonist treatment enhances participation of FGFR1 and 5-HT1A homodimers and recruitment of β-arrestin2

Biochem Biophys Res Commun. 2013 Nov 15;441(2):387-92. doi: 10.1016/j.bbrc.2013.10.067. Epub 2013 Oct 21.

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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology*
  • Arrestins / metabolism*
  • Fibroblast Growth Factor 2 / pharmacology
  • HEK293 Cells
  • Humans
  • Protein Conformation
  • Protein Multimerization
  • Receptor, Fibroblast Growth Factor, Type 1 / agonists
  • Receptor, Fibroblast Growth Factor, Type 1 / chemistry
  • Receptor, Fibroblast Growth Factor, Type 1 / metabolism*
  • Receptor, Serotonin, 5-HT1A / chemistry
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Serotonin Receptor Agonists / pharmacology*
  • beta-Arrestins

Substances

  • Arrestins
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Receptor Agonists
  • beta-Arrestins
  • Fibroblast Growth Factor 2
  • Receptor, Serotonin, 5-HT1A
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • FGFR1 protein, human
  • Receptor, Fibroblast Growth Factor, Type 1