title: 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.affiliation: Department of Internal Medicine and Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Sachin
authors.initials: S
authors.lastname: Hajarnis
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Ma
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Chapin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caplan
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
authors.forename: Stefan
authors.initials: S
authors.lastname: Somlo
authors.forename: Peter
authors.initials: P
authors.lastname: Igarashi
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002923:Cilia / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D052177:Kidney Diseases, Cystic / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000378:metabolism*
chemical_list: D054758:A Kinase Anchor Proteins; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D050396:TRPP Cation Channels