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bioRxiv · 10.64898/2026.10.05.756873

Primary cilia facilitate GPCR neurotransmission through the canonical cAMP cascade

Fagan, R. R.·He, X. J.·Stuurman, N.·Ehrlich, A. T.·Von Zastrow, M.
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Abstract

The primary cilium is increasingly recognized to be a discrete site for initiating neurotransmission through G protein-coupled receptors (GPCRs), yet how such neurotransmission is propagated downstream remains unclear. A canonical pathway of downstream GPCR neurotransmission is the cyclic AMP (cAMP) / cAMP-dependent protein kinase (PKA) cascade. While cAMP can be locally generated in cilia and produce important effects that are functionally compartmentalized there, neurotransmission through GPCRs must propagate to effectors outside of cilia. Thus, a prevailing current view is that ciliary neurotransmission is restricted to non-canonical, cAMP-dependent pathways. Revisiting this view, we show here that the primary cilium of striatal medium spiny neurons is a major site from which endogenous D1 dopamine receptors initiate cAMP and PKA activity elevations that propagate throughout the extraciliary cytoplasm. We also show that the primary cilium spatially aligns essentially this entire long-range signaling axis from intercalating with numerous dopaminergic axon varicosities that initiate neurotransmission to enforcing proximity with somatic PKA stores that are activated by cAMP downstream. Together, these results extend the concept of ciliary neurotransmission to dopaminergic signaling in striatal neurons and reveal that, in this system, the primary cilium facilitates rather than restricts neurotransmission through the canonical cAMP / PKA cascade.

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Fagan, R. R., He, X. J., Stuurman, N., Ehrlich, A. T., Von Zastrow, M.. 2026-10-12. Primary cilia facilitate GPCR neurotransmission through the canonical cAMP cascade. https://doi.org/10.64898/2026.10.05.756873

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