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PKD2 Functions as an Epidermal Growth Factor-Activated Plasma Membrane Channel
Rong Ma,1,
Wei-Ping Li,1,
Dana Rundle,1,¶
Jin Kong,1
Hamid I. Akbarali,2, and
Leonidas Tsiokas1*
Department of Cell Biology, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73104,1
Department of Physiology, University of Oklahoma Health Sciences Center, 941 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 731042
Received for publication 20 September 2004.
Revision received 24 November 2004.
Accepted for publication 5 July 2005.
Abstract:
PKD2, or polycystin 2, the product of the gene mutated in type2 autosomal dominant polycystic kidney disease, belongs to thetransient receptor potential channel superfamily and has beenshown to function as a nonselective cation channel in the plasmamembrane. However, the mechanism of PKD2 activation remainselusive. We show that PKD2 overexpression increases epidermalgrowth factor (EGF)-induced inward currents in LLC-PK1 kidneyepithelial cells, while the knockdown of endogenous PKD2 byRNA interference or the expression of a pathogenic missensevariant, PKD2-D511V, blunts the EGF-induced response. Pharmacologicalexperiments indicate that the EGF-induced activation of PKD2occurs independently of store depletion but requires the activityof phospholipase C (PLC) and phosphoinositide 3-kinase (PI3K).Pipette infusion of purified phosphatidylinositol-4,5-bisphosphate(PIP2) suppresses the PKD2-mediated effect on EGF-induced conductance,while pipette infusion of phosphatidylinositol-3,4,5-trisphosphate(PIP3) does not have any effect on this conductance. Overexpressionof type I phosphatidylinositol-4-phosphate 5-kinase [PIP(5)K],which catalyzes the formation of PIP2, suppresses EGF-inducedcurrents. Biochemical experiments show that PKD2 physicallyinteracts with PLC-2 and EGF receptor (EGFR) in transfectedHEK293T cells and colocalizes with EGFR and PIP2 in the primarycilium of LLC-PK1 cells. We propose that plasma membrane PKD2is under negative regulation by PIP2. EGF may reduce the thresholdof PKD2 activation by mechanical and other stimuli by releasingit from PIP2-mediated inhibition.
* Corresponding author. Mailing address: University of Oklahoma Health Sciences Center, BSEB302E, 941 Stanton L. Young Boulevard, Oklahoma City, OK 73104. Phone: (405) 271-8001, ext. 46211. Fax: (405) 271-3758. E-mail: leonidas-tsiokas{at}ouhsc.edu.
Present address: Department of Integrative Physiology, Universityof North Texas Health Science Center at Fort Worth, 3500 CampBowie Boulevard, Fort Worth, TX 76107-2699.
Present address: Department of Pharmacology, Anhui Medical University,Hefei, People's Republic of China.
¶ Present address: Department of Chemistry, University of CentralOklahoma, 100 North University Drive, Edmond, OK 73034.
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Wei-Ping Li,1
Dana Rundle,1
phosphatidylinositol-4-phosphate 5-kinase [PIP(5)K
2 and EGF receptor (EGFR) in transfected HEK293T cells and colocalizes with EGFR and PIP2 in the primary cilium of LLC-PK1 cells. We propose that plasma membrane PKD2 is under negative regulation by PIP2. EGF may reduce the threshold of PKD2 activation by mechanical and other stimuli by releasing it from PIP2-mediated inhibition. 
Supplemental material for this article may be found at 
Present address: Department of Integrative Physiology, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699. 
Present address: Department of Pharmacology, Anhui Medical University, Hefei, People's Republic of China. 
