Research ArticleGPCR SIGNALING

Dynamic interactions of the 5-HT6 receptor with protein partners control dendritic tree morphogenesis

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Science Signaling  11 Feb 2020:
Vol. 13, Issue 618, eaax9520
DOI: 10.1126/scisignal.aax9520

Taking the time to signal

The serotonin receptor 5-HT6R is a GPCR exclusively found in the nervous system that has emerged as a potential therapeutic target in various neurological disorders. Although preliminary studies suggested that 5-HT6R antagonists have procognitive effects, clinical trials have been disappointing. Pujol et al. analyzed the dynamics of 5-HT6R interactions with other proteins and found that after its previously characterized interaction with and phosphorylation by the kinase Cdk5, the 5-HT6R interacted with GPRIN1, a promoter of neurite extension. These sequential interactions enhanced 5-HT6R constitutive activity, promoting neurite extension and branching in neuroblastoma cells and primary striatal neurons. The GPRIN1–5-HT6R interaction was reduced by 5-HT6R antagonist, suggesting that the dynamic interactions of this receptor are regulated by its conformational state.


The serotonin (5-hydroxytrypatmine) receptor 5-HT6 (5-HT6R) has emerged as a promising target to alleviate the cognitive symptoms of neurodevelopmental diseases. We previously demonstrated that 5-HT6R finely controls key neurodevelopmental steps, including neuronal migration and the initiation of neurite growth, through its interaction with cyclin-dependent kinase 5 (Cdk5). Here, we showed that 5-HT6R recruited G protein–regulated inducer of neurite outgrowth 1 (GPRIN1) through a Gs-dependent mechanism. Interactions between the receptor and either Cdk5 or GPRIN1 occurred sequentially during neuronal differentiation. The 5-HT6R–GPRIN1 interaction enhanced agonist-independent, receptor-stimulated cAMP production without altering the agonist-dependent response in NG108-15 neuroblastoma cells. This interaction also promoted neurite extension and branching in NG108-15 cells and primary mouse striatal neurons through a cAMP-dependent protein kinase A (PKA)–dependent mechanism. This study highlights the complex allosteric modulation of GPCRs by protein partners and demonstrates how dynamic interactions between GPCRs and their protein partners can control the different steps of highly coordinated cellular processes, such as dendritic tree morphogenesis.

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