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Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking
Ute Renner, Andre Zeug, Andrew Woehler, Marcus Niebert, Alexander Dityatev, Galina Dityateva, Nataliya Gorinski, Daria Guseva, Dalia Abdel-Galil, Matthias Fröhlich, Frank Döring, Erhard Wischmeyer, Diethelm W. Richter, Erwin Neher, Evgeni G. Ponimaskin


Serotonin receptors 5-HT1A and 5-HT7 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-HT1A and 5-HT7 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-HT1A or 5-HT7 receptors together with monomers coexist in cells. The highest affinity for complex formation was obtained for the 5-HT7–5-HT7 homodimers, followed by the 5-HT7–5-HT1A heterodimers and 5-HT1A–5-HT1A homodimers. Functionally, heterodimerization decreases 5-HT1A-receptor-mediated activation of Gi protein without affecting 5-HT7-receptor-mediated signalling. Moreover, heterodimerization markedly decreases the ability of the 5-HT1A 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-HT1A receptor internalization and also enhances the ability of the 5-HT1A receptor to activate the mitogen-activated protein kinases. Finally, we found that production of 5-HT7 receptors in the hippocampus continuously decreases during postnatal development, indicating that the relative concentration of 5-HT1A–5-HT7 heterodimers and, consequently, their functional importance undergoes pronounced developmental changes.


  • * These authors contributed equally to this work

  • Funding

    These studies were supported by the Deutsche Forschungsgemeinschaft (DFG) [grant number PO732] and through the Centre of Molecular Physiology of the Brain (CMPB) to E.G.P., D.W.R. and E.N. A.Z. was supported by the Federal Ministry of Education and Research (BMBF) [grant number 0315690D].

  • Supplementary material available online at

  • Accepted January 11, 2012.
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