title: TRPP2 channels regulate apoptosis through the Ca2+ concentration in the endoplasmic reticulum.
abstract: Ca(2+) is an important signalling molecule that regulates multiple cellular processes, including apoptosis. Although Ca(2+) influx through transient receptor potential (TRP) channels in the plasma membrane is known to trigger cell death, the function of intracellular TRP proteins in the regulation of Ca(2+)-dependent signalling pathways and apoptosis has remained elusive. Here, we show that TRPP2, the ion channel mutated in autosomal dominant polycystic kidney disease (ADPKD), protects cells from apoptosis by lowering the Ca(2+) concentration in the endoplasmic reticulum (ER). ER-resident TRPP2 counteracts the activity of the sarcoendoplasmic Ca(2+) ATPase by increasing the ER Ca(2+) permeability. This results in diminished cytosolic and mitochondrial Ca(2+) signals upon stimulation of inositol 1,4,5-trisphosphate receptors and reduces Ca(2+) release from the ER in response to apoptotic stimuli. Conversely, knockdown of TRPP2 in renal epithelial cells increases ER Ca(2+) release and augments sensitivity to apoptosis. Our findings indicate an important function of ER-resident TRPP2 in the modulation of intracellular Ca(2+) signalling, and provide a molecular mechanism for the increased apoptosis rates in ADPKD upon loss of TRPP2 channel function.
authors.affiliation: Renal Division, University Hospital of Freiburg, Freiburg, Germany.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wegierski
authors.forename: Daniel
authors.initials: D
authors.lastname: Steffl
authors.forename: Christoph
authors.initials: C
authors.lastname: Kopp
authors.forename: Robert
authors.initials: R
authors.lastname: Tauber
authors.forename: Björn
authors.initials: B
authors.lastname: Buchholz
authors.forename: Roland
authors.initials: R
authors.lastname: Nitschke
authors.forename: E Wolfgang
authors.initials: EW
authors.lastname: Kuehn
authors.forename: Gerd
authors.initials: G
authors.lastname: Walz
authors.forename: Michael
authors.initials: M
authors.lastname: Köttgen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology; D002460:Cell Line; D003600:Cytosol / Q000502:physiology; D004285:Dogs; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005260:Female; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D015640:Ion Channel Gating / Q000502:physiology*; D008928:Mitochondria / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000502:physiology; D050396:TRPP Cation Channels / Q000502:physiology*; D014981:Xenopus
chemical_list: D002118:Calcium; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D050396:TRPP Cation Channels