Activation of the endothelial store-operated ISOC Ca2+ channel requires interaction of protein 4.1 with TRPC4

Circ Res. 2005 Nov 25;97(11):1164-72. doi: 10.1161/01.RES.0000193597.65217.00. Epub 2005 Oct 27.


Store-operated calcium (SOC) entry represents the principal Ca2+ entry pathway into nonexcitable cells. Despite intensive investigation, mechanisms underlying activation of SOC entry have remained elusive. The endothelial ISOC channel is a Ca2+-selective SOC entry channel to which the transient receptor potential (TRP) proteins TRPC1 and TRPC4 contribute subunits. Activation of ISOC is specifically regulated by the spectrin-actin membrane skeleton; however, the nature of coupling between the ISOC channel and membrane skeleton is unknown. Here we demonstrate that protein 4.1 is an essential component of the ISOC channel gating mechanism. Protein 4.1 interacts with TRPC4 and the membrane skeleton. Deletion of the protein 4.1 binding domain on TRPC4 or peptide competition to the protein 4.1 binding domain prevents ISOC activation. These findings reveal that interaction of protein 4.1 with TRPC4 is required for activation of the endothelial ISOC channel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Blood Proteins / chemistry
  • Blood Proteins / physiology*
  • Calcium Channels / physiology*
  • Cell Adhesion
  • Cells, Cultured
  • Cytoskeletal Proteins
  • Endothelial Cells / metabolism*
  • Humans
  • Ion Channel Gating
  • Membrane Proteins
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / physiology*
  • Potassium Iodide / pharmacology
  • Pulmonary Artery / metabolism
  • TRPC Cation Channels / physiology*


  • Blood Proteins
  • Calcium Channels
  • Cytoskeletal Proteins
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • TRPC Cation Channels
  • TRPC4 ion channel
  • erythrocyte membrane band 4.1 protein
  • Potassium Iodide