title: TRPP2 and TRPV4 form an EGF-activated calcium permeable channel at the apical membrane of renal collecting duct cells.
abstract: OBJECTIVE
  Regulation of apical calcium entry is important for the function of principal cells of the collecting duct. However, the molecular identity and the regulators of the transporter/channel, which is responsible for apical calcium entry and what factors regulate the calcium conduction remain unclear.
  
  
  RESULTS
  We report that endogenous TRPP2 and TRPV4 assemble to form a 23-pS divalent cation-permeable non-selective ion channel at the apical membrane of renal principal cells of the collecting duct. TRPP2\TRPV4 channel complex was identified by patch-clamp, immunofluorescence and co-immunprecipitation studies in both principal cells that either possess normal cilia (cilia (+)) or in which cilia are absent (cilia (-)). This channel has distinct biophysical and pharmacological and regulatory profiles compared to either TRPP2 or TRPV4 channels. The rate of occurrence detected by patch clamp was higher in cilia (-) compared to cilia (+) cells. In addition, shRNA knockdown of TRPP2 increased the prevalence of TRPV4 channel activity while knockdown of TRPV4 resulted in TRPP2 activity and knockdown of both proteins vastly decreased the 23-pS channel activity. Epidermal growth factor (EGF) stimulated TRPP2\TRPV4 channel through the EGF receptor (EGFR) tyrosine kinase-dependent signaling. With loss of cilia, apical EGF treatment resulted in 64-fold increase in channel activity in cilia (-) but not cilia (+) cells. In addition EGF increased cell proliferation in cilia (-) cell that was dependent upon TRPP2\TRPV4 channel mediated increase in intracellular calcium.
  
  
  CONCLUSIONS
  We conclude that in the absence of cilia, an EGF activated TRPP2\TRPV4 channel may play an important role in increased cell proliferation and cystogenesis.
authors: Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors: Zhi-Ren
authors: ZR
authors: Zhang
authors: Wen-Feng
authors: WF
authors: Chu
authors: Binlin
authors: B
authors: Song
authors: Monika
authors: M
authors: Gooz
authors: Jia-Ning
authors: JN
authors: Zhang
authors: Chang-Jiang
authors: CJ
authors: Yu
authors: Shuai
authors: S
authors: Jiang
authors: Aleksander
authors: A
authors: Baldys
authors: Pal
authors: P
authors: Gooz
authors: Stacy
authors: S
authors: Steele
authors: Grzegorz
authors: G
authors: Owsianik
authors: Bernd
authors: B
authors: Nilius
authors: Peter
authors: P
authors: Komlosi
authors: P Darwin
authors: PD
authors: Bell
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002413:Cations, Divalent / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects*; D016764:Cell Polarity / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002923:Cilia / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D020868:Gene Silencing / Q000187:drug effects; D047468:Immunoprecipitation; D015640:Ion Channel Gating / Q000187:drug effects; D007685:Kidney Tubules, Collecting / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D050396:TRPP Cation Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: D002118:Calcium; D002120:Calcium Channel Agonists; D002413:Cations, Divalent; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D050396:TRPP Cation Channels; D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse
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