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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 Tsiokas^1*

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 20 September 2004/ Returned for modification 24 November 2004/ Accepted 5 July 2005

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 phosphatidylinositol-4-phosphate 5-kinase [PIP(5)K], which catalyzes the formation of PIP₂, suppresses EGF-induced currents. Biochemical experiments show that PKD2 physically interacts with PLC-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 http://mcb.asm.org/.

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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