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Journal Article

Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking.

MPS-Authors
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Woehler,  A.
Emeritus Group of Membrane Biophysics, MPI for Biophysical Chemistry, Max Planck Society;

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Neher,  E.
Emeritus Group of Membrane Biophysics, MPI for Biophysical Chemistry, Max Planck Society;

External Ressource
Fulltext (public)

1481617.pdf
(Publisher version), 3MB

Supplementary Material (public)

1481617_S1-S5.pdf
(Supplementary material), 737KB

Citation

Renner, U., Zeug, A., Woehler, A., Niebert, M., Dityatev, A., Dityateva, G., et al. (2012). Heterodimerization of serotonin receptors 5-HT1A and 5-HT7 differentially regulates receptor signalling and trafficking. Journal of Cell Science, 125(10), 2486-2499. doi:10.1242/jcs.101337.


Cite as: http://hdl.handle.net/11858/00-001M-0000-000F-A828-A
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