title: Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking.
abstract: Serotonin receptors 5-HT(1A) and 5-HT(7) are highly coexpressed in brain regions implicated in depression. However, their functional interaction has not been established. In the present study we show that 5-HT(1A) and 5-HT(7) receptors form heterodimers both in vitro and in vivo. Foerster resonance energy transfer-based assays revealed that, in addition to heterodimers, homodimers composed either of 5-HT(1A) or 5-HT(7) receptors together with monomers coexist in cells. The highest affinity for complex formation was obtained for the 5-HT(7)-5-HT(7) homodimers, followed by the 5-HT(7)-5-HT(1A) heterodimers and 5-HT(1A)-5-HT(1A) homodimers. Functionally, heterodimerization decreases 5-HT(1A)-receptor-mediated activation of G(i) protein without affecting 5-HT(7)-receptor-mediated signalling. Moreover, heterodimerization markedly decreases the ability of the 5-HT(1A) receptor to activate G-protein-gated inwardly rectifying potassium channels in a heterologous system. The inhibitory effect on such channels was also preserved in hippocampal neurons, demonstrating a physiological relevance of heteromerization in vivo. In addition, heterodimerization is crucially involved in initiation of the serotonin-mediated 5-HT(1A) receptor internalization and also enhances the ability of the 5-HT(1A) receptor to activate the mitogen-activated protein kinases. Finally, we found that production of 5-HT(7) receptors in the hippocampus continuously decreases during postnatal development, indicating that the relative concentration of 5-HT(1A)-5-HT(7) heterodimers and, consequently, their functional importance undergoes pronounced developmental changes.
authors.affiliation: DFG-Research Center Molecular Physiology of the Brain (CMPB), 37077 Göttingen,  Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Renner
authors.forename: Andre
authors.initials: A
authors.lastname: Zeug
authors.forename: Andrew
authors.initials: A
authors.lastname: Woehler
authors.forename: Marcus
authors.initials: M
authors.lastname: Niebert
authors.forename: Alexander
authors.initials: A
authors.lastname: Dityatev
authors.forename: Galina
authors.initials: G
authors.lastname: Dityateva
authors.forename: Nataliya
authors.initials: N
authors.lastname: Gorinski
authors.forename: Daria
authors.initials: D
authors.lastname: Guseva
authors.forename: Dalia
authors.initials: D
authors.lastname: Abdel-Galil
authors.forename: Matthias
authors.initials: M
authors.lastname: Fröhlich
authors.forename: Frank
authors.initials: F
authors.lastname: Döring
authors.forename: Erhard
authors.initials: E
authors.lastname: Wischmeyer
authors.forename: Diethelm W
authors.initials: DW
authors.lastname: Richter
authors.forename: Erwin
authors.initials: E
authors.lastname: Neher
authors.forename: Evgeni G
authors.initials: EG
authors.lastname: Ponimaskin
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D019281:Dimerization; D051379:Mice; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D011985:Receptors, Serotonin; C104425:serotonin 7 receptor; D044282:Receptor, Serotonin, 5-HT1A