Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases

Yun Hee Choi, Akira Suzuki, Sachin Hajarnis, Ma Zhendong, Hannah C. Chapin, Michael J. Caplan, Marco Pontoglio, Stefan Somlo, Peter Igarashi

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Polycystic kidney disease (PKD) is a genetic disorder that is characterized by cyst formation in kidney tubules. PKD arises from abnormalities of the primary cilium, a sensory organelle located on the cell surface. Here, we show that the primary cilium of renal epithelial cells contains a protein complex comprising adenylyl cyclase 5/6 (AC5/6), A-kinase anchoring protein 150 (AKAP150), and protein kinase A. Loss of primary cilia caused by deletion of Kif3a results in activation of AC5 and increased cAMP levels. Polycystin-2 (PC2), a ciliary calcium channel that is mutated in human PKD, interacts with AC5/6 through its C terminus. Deletion of PC2 increases cAMP levels, which can be corrected by reexpression of wild-type PC2 but not by a mutant lacking calcium channel activity. Phosphodiesterase 4C (PDE4C), which catabolizes cAMP, is also located in renal primary cilia and interacts with the AKAP150 complex. Expression of PDE4C is regulated by the transcription factor hepatocyte nuclear factor-1β (HNF-1β), mutations of which produce kidney cysts. PDE4C is down-regulated and cAMP levels are increased in HNF-1β mutant kidney cells and mice. Collectively, these findings identify PC2 and PDE4C as unique components of an AKAP complex in primary cilia and reveal a common mechanism for dysregulation of cAMP signaling in cystic kidney diseases arising from different gene mutations.

Original languageEnglish (US)
Pages (from-to)10679-10684
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number26
DOIs
StatePublished - Jun 28 2011

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Type 4 Cyclic Nucleotide Phosphodiesterase
Cystic Kidney Diseases
Cilia
Protein Kinases
Polycystic Kidney Diseases
Hepatocyte Nuclear Factor 1
Kidney
Calcium Channels
Cysts
Kidney Tubules
Mutation
Inborn Genetic Diseases
Cyclic AMP-Dependent Protein Kinases
Organelles
Epithelial Cells
2'-phosphodiesterase
polycystic kidney disease 2 protein
Genes
Proteins

Keywords

  • Cyclic AMP
  • Intraflagellar transport
  • PKD2
  • TCF2
  • vHNF1

ASJC Scopus subject areas

  • General

Cite this

Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases. / Choi, Yun Hee; Suzuki, Akira; Hajarnis, Sachin; Zhendong, Ma; Chapin, Hannah C.; Caplan, Michael J.; Pontoglio, Marco; Somlo, Stefan; Igarashi, Peter.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 26, 28.06.2011, p. 10679-10684.

Research output: Contribution to journalArticle

Choi, Yun Hee ; Suzuki, Akira ; Hajarnis, Sachin ; Zhendong, Ma ; Chapin, Hannah C. ; Caplan, Michael J. ; Pontoglio, Marco ; Somlo, Stefan ; Igarashi, Peter. / Polycystin-2 and phosphodiesterase 4C are components of a ciliary A-kinase anchoring protein complex that is disrupted in cystic kidney diseases. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 26. pp. 10679-10684.
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AU - Choi, Yun Hee

AU - Suzuki, Akira

AU - Hajarnis, Sachin

AU - Zhendong, Ma

AU - Chapin, Hannah C.

AU - Caplan, Michael J.

AU - Pontoglio, Marco

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AU - Igarashi, Peter

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