PKD2 functions as an epidermal growth factor-activated plasma membrane channel

Rong Ma, Wei Ping Li, Dana Rundle, Jin Kong, Hamid I. Akbarali, Leonidas Tsiokas

Research output: Contribution to journalArticle

121 Citations (Scopus)

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 super-family 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 Iα phosphatidylinositol-4-phosphate 5-kinase [PIP(5)Kα], which catalyzes the formation of PIP2, suppresses EGF-induced currents. Biochemical experiments show that PKD2 physically interacts with PLC-γ2 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.

Original languageEnglish
Pages (from-to)8285-8298
Number of pages14
JournalMolecular and Cellular Biology
Volume25
Issue number18
DOIs
StatePublished - 1 Sep 2005

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Ion Channels
Epidermal Growth Factor
Cell Membrane
Type C Phospholipases
Epidermal Growth Factor Receptor
LLC-PK1 Cells
Transient Receptor Potential Channels
Autosomal Dominant Polycystic Kidney
1-Phosphatidylinositol 4-Kinase
Cilia
Phosphatidylinositols
RNA Interference
Cations
Epithelial Cells
Pharmacology
Kidney
Genes

Cite this

Ma, Rong ; Li, Wei Ping ; Rundle, Dana ; Kong, Jin ; Akbarali, Hamid I. ; Tsiokas, Leonidas. / PKD2 functions as an epidermal growth factor-activated plasma membrane channel. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 18. pp. 8285-8298.
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PKD2 functions as an epidermal growth factor-activated plasma membrane channel. / Ma, Rong; Li, Wei Ping; Rundle, Dana; Kong, Jin; Akbarali, Hamid I.; Tsiokas, Leonidas.

In: Molecular and Cellular Biology, Vol. 25, No. 18, 01.09.2005, p. 8285-8298.

Research output: Contribution to journalArticle

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