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Related Experiment Video

Updated: Nov 7, 2025

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Vertebrate cells differentially interpret ciliary and extraciliary cAMP.

Melissa E Truong1, Sara Bilekova2, Semil P Choksi1

  • 1Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.

Cell
|May 1, 2021
PubMed
Summary

Cells differentiate between signaling in the primary cilium and cytoplasm. Ciliary cyclic AMP (cAMP) inhibits Hedgehog signaling via a specific protein kinase A (PKA) pool, demonstrating spatial signaling distinctness.

Keywords:
G protein-coupled receptorHedgehog signalingcAMPchemogeneticsdevelopmentoptogeneticsprimary ciliaprotein kinase Asignal transduction

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Area of Science:

  • Cell Biology
  • Molecular Signaling
  • Organelle Function

Background:

  • G protein-coupled receptors (GPCRs) and Hedgehog pathway components are found in primary cilia.
  • The primary cilium is crucial for cellular signal transduction.
  • GPCR signaling occurs both inside and outside the primary cilium.

Purpose of the Study:

  • To determine if cells differentiate between signaling from G protein-coupled receptors (GPCRs) located in the primary cilium versus those outside.
  • To investigate if ciliary and extraciliary cyclic AMP (cAMP) transmit distinct information.
  • To identify the mechanisms cells use to distinguish subcellular signaling events.

Main Methods:

  • Engineered optogenetic and chemogenetic tools to control cyclic AMP (cAMP) generation at specific subcellular locations.
  • Generated equal amounts of ciliary and cytoplasmic cAMP in zebrafish and mammalian cell models.
  • Utilized modeling to understand the impact of distinct cellular geometries on effector activation.
  • Identified and functionally tested ciliary and extraciliary pools of protein kinase A (PKA).

Main Results:

  • Ciliary cAMP, but not cytoplasmic cAMP, inhibited Hedgehog signaling.
  • Distinct cellular geometries of the cilium and cell body were suggested to differentially activate local effectors.
  • A specific pool of protein kinase A (PKA) was identified within the cilium.
  • Blocking ciliary PKA, but not extraciliary PKA, activated Hedgehog signaling and reversed ciliary cAMP effects.

Conclusions:

  • Cells distinguish between ciliary and extraciliary cyclic AMP (cAMP) signals.
  • Functionally and spatially distinct pools of protein kinase A (PKA) mediate this cellular discrimination.
  • Different subcellular pools of cAMP convey unique information, impacting downstream signaling pathways like Hedgehog.