Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics

Research output: Contribution to journalArticle

Abstract

Protein kinase A (PKA) phosphorylates Gli proteins, acting as a negative regulator of the Hedgehog pathway. PKA was recently detected within the cilium, and PKA activity specifically in cilia regulates Gli processing. Using a cilia-targeted genetically encoded sensor, we found significant basal PKA activity. Using another targeted sensor, we measured basal ciliary cAMP that is fivefold higher than whole-cell cAMP. The elevated basal ciliary cAMP level is a result of adenylyl cyclase 5 and 6 activity that depends on ciliary phosphatidylinositol (3,4,5)-trisphosphate (PIP3), not stimulatory G protein (Gαs), signaling. Sonic Hedgehog (SHH) reduces ciliary cAMP levels, inhibits ciliary PKA activity, and increases Gli1. Remarkably, SHH regulation of ciliary cAMP and downstream signals is not dependent on inhibitory G protein (Gαi/o) signaling but rather Ca2+ entry through a Gd3+-sensitive channel. Therefore, PIP3 sustains high basal cAMP that maintains PKA activity in cilia and Gli repression. SHH activates Gli by inhibiting cAMP through a G protein-independent mechanism that requires extracellular Ca2+ entry.

Original languageEnglish (US)
Pages (from-to)13069-13074
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number46
DOIs
StatePublished - Nov 15 2016
Externally publishedYes

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Keywords

  • CAMP
  • Cilia
  • Hedgehog
  • PIP
  • PKA

ASJC Scopus subject areas

  • General

Cite this

Moore, B. S., Stepanchick, A. N., Tewson, P. H., Hartle, C. M., Zhang, J., Quinn, A. M., Hughes, T. E., & Mirshahi, T. (2016). Cilia have high cAMP levels that are inhibited by Sonic Hedgehog-regulated calcium dynamics. Proceedings of the National Academy of Sciences of the United States of America, 113(46), 13069-13074. https://doi.org/10.1073/pnas.1602393113