Evidence map›Paper›PMID 42268917›Full record

ArticlePLoS biology2026

Smoothened and ciliary GPCRs regulate ciliary protein kinase A activity involved in Hedgehog signal transduction.

Thi D Nguyen, Mia J Konjikusic, Lorenzo M Del Castillo, Roshanak Irannejad, Jeremy F Reiter

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in PLoS biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors.

Thi D NguyenDepartment of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, California, United States of America.ORCID https://orcid.org/0000-0001-7525-920X
Mia J KonjikusicDepartment of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, California, United States of America.
Lorenzo M Del CastilloDepartment of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, California, United States of America.
Roshanak IrannejadDepartment of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, California, United States of America.
Jeremy F ReiterDepartment of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, California, United States of America.ORCID https://orcid.org/0000-0002-6512-320X

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Hedgehog (HH) signaling in vertebrates is dependent on the primary cilium, an organelle that scaffolds signal transduction. HH signals induce ciliary enrichment of Smoothened (SMO) and ciliary departure of the G protein-coupled receptor (GPCR) GPR161 to trigger GLI activation of the HH transcriptional program. Recently, SMO has been shown to inhibit protein kinase A (PKA). To test the hypothesis that SMO inhibits PKA at cilia to activate the HH signal transduction pathway, we developed a ciliary PKA reporter. Ciliary PKA activity was graded during zebrafish development. Activation of the HH signal transduction pathway by either Sonic hedgehog (SHH) or SMO agonist (SAG) inhibited ciliary PKA activity. Blocking SMO phosphorylation by GRK2/3 prevented ciliary SMO from inhibiting ciliary PKA activity. Converting the SMO C-terminal PKA pseudosubstrate site into a consensus PKA substrate blocked SMO-mediated inhibition of ciliary PKA activity. A ciliary GPCR, SSTR3, activated ciliary PKA and induced HH transcriptional responses in NIH/3T3 cells via a different mechanism: activation of Gαi/o. A different ciliary GPCR, GPR161, possesses an A-Kinase Anchoring Protein (AKAP), which we found was critical for the ciliary localization of the catalytic subunit of PKA (PKA-C) to promote ciliary PKA activity. We propose that HH signal transduction is inhibited by GPR161-mediated ciliary enrichment of PKA-C, and activated by GRK2/3-phosphorylated SMO inhibition of ciliary PKA activity.

Indexed as

CiliaCyclic AMP-Dependent Protein KinasesHedgehog ProteinsReceptors, G-Protein-CoupledReceptors, SomatostatinSignal TransductionZebrafish ProteinsAnimalsG-Protein-Coupled Receptor Kinase 2HumansMiceNIH 3T3 CellsPhosphorylationSmoothened ReceptorZebrafishCyclic AMP-Dependent Protein KinasesG-Protein-Coupled Receptor Kinase 2Hedgehog ProteinsReceptors, G-Protein-CoupledReceptors, SomatostatinSmoothened Receptorsmo protein, zebrafishsomatostatin receptor 3Zebrafish Proteins

Identifiers

PMID42268917
PMCPMC13289941

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.