Serotonin signals through ciliary 5-HT6 to control insulin secretion

Townsend, S. E.; Jo, J. H.; Opp, M.; Bates, K.; Dong, X.; Hughes, J. W.

doi:10.64898/2026.10.30.763155

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bioRxiv · 10.64898/2026.10.30.763155

Serotonin signals through ciliary 5-HT6 to control insulin secretion

Townsend, S. E.·Jo, J. H.·Opp, M.·Bates, K.·Dong, X.·Hughes, J. W.

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Abstract

In the pancreatic islet, serotonin (5-HT) functions basally to modulate glucagon secretion, but its contribution to beta-cell signaling and function remains unclear. Here, we demonstrate that the Gs-coupled serotonin receptor 6 (5-HT6), previously thought to be expressed almost exclusively in the brain, localizes to the primary cilium and plasma membrane of islet cells and augments insulin secretion. Utilizing a transgenic model of beta-cell cilia loss, along with approaches to perturb cilia-specific 5-HT6 function without disrupting the native cilium architecture, we show that 5-HT6 action in beta cells is dependent on the primary cilium. Critically, the plasma membrane pool of 5-HT6 cannot stimulate insulin release when the cilium is absent, representing an instance of whole-cell regulation by a cilia-localized GPCR. These findings establish subcellular localization as a determinant of GPCR function in beta cells and identify ciliary 5-HT6 signaling as a distinct pathway for modulating insulin secretion.

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Townsend, S. E., Jo, J. H., Opp, M., Bates, K., Dong, X., Hughes, J. W.. 2026-11-03. Serotonin signals through ciliary 5-HT6 to control insulin secretion. https://doi.org/10.64898/2026.10.30.763155

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