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Free keywords:
G-protein coupled receptor, Oligomerization, Signal transduction
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
