TRPP2 and TRPV4 form an EGF-activated calcium permeable channel at the apical membrane of renal collecting duct cells.

Academic Article

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. METHODS AND 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. CONCLUSION: 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

    Published In

  • PLoS ONE  Journal
  • Keywords

  • Animals, Calcium, Calcium Channel Agonists, Cations, Divalent, Cell Membrane Permeability, Cell Polarity, Cell Proliferation, Cilia, Epidermal Growth Factor, ErbB Receptors, Extracellular Signal-Regulated MAP Kinases, Fluorescent Antibody Technique, Gene Silencing, Immunoprecipitation, Ion Channel Gating, Kidney Tubules, Collecting, MAP Kinase Signaling System, Mice, Phosphorylation, TRPP Cation Channels, TRPV Cation Channels
  • Digital Object Identifier (doi)

    Author List

  • Zhang Z-R; Chu W-F; Song B; Gooz M; Zhang J-N; Yu C-J; Jiang S; Baldys A; Gooz P; Steele S
  • Start Page

  • e73424
  • Volume

  • 8
  • Issue

  • 8