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

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.

• Authors: Yun-Hee Choi, Akira Suzuki, Sachin Hajarnis, Zhendong Ma, Hannah C Chapin, Michael J Caplan, Marco Pontoglio, Stefan Somlo, Peter Igarashi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 26 Pg. 10679-84 (Jun 28 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21670265 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• A Kinase Anchor Proteins
• TRPP Cation Channels
• polycystic kidney disease 2 protein
• Cyclic AMP
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• A Kinase Anchor Proteins (genetics, metabolism)
• Animals
• Cilia (metabolism)
• Cyclic AMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
• Immunoenzyme Techniques
• Kidney Diseases, Cystic (metabolism)
• Mice
• Mutation
• Signal Transduction
• TRPP Cation Channels (metabolism)