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Mol. Cell. Biol. 25 (18): 8285-8298

Copyright © 2005 by the American Society for Microbiology. All rights reserved.

PKD2 Functions as an Epidermal Growth Factor-Activated Plasma Membrane Channel{dagger}

Rong Ma,1,{ddagger} 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 type 2 autosomal dominant polycystic kidney disease, belongs to the transient receptor potential channel superfamily and has been shown to function as a nonselective cation channel in the plasma membrane. However, the mechanism of PKD2 activation remains elusive. We show that PKD2 overexpression increases epidermal growth factor (EGF)-induced inward currents in LLC-PK1 kidney epithelial cells, while the knockdown of endogenous PKD2 by RNA interference or the expression of a pathogenic missense variant, PKD2-D511V, blunts the EGF-induced response. Pharmacological experiments indicate that the EGF-induced activation of PKD2 occurs independently of store depletion but requires the activity of 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. Overexpression of type I{alpha} phosphatidylinositol-4-phosphate 5-kinase [PIP(5)K{alpha}], which catalyzes the formation of PIP2, suppresses EGF-induced currents. Biochemical experiments show that PKD2 physically interacts with PLC-{gamma}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.

* 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}

{dagger} Supplemental material for this article may be found at

{ddagger} 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.

Present address: Department of Chemistry, University of Central Oklahoma, 100 North University Drive, Edmond, OK 73034.

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