Functional interaction between InsP3 receptors and store-operated Htrp3 channels

Nature. 1998 Dec 3;396(6710):478-82. doi: 10.1038/24890.


Calcium ions are released from intracellular stores in response to agonist-stimulated production of inositol 1,4,5-trisphosphate (InsP3), a second messenger generated at the cell membrane. Depletion of Ca2+ from internal stores triggers a capacitative influx of extracellular Ca2+ across the plasma membrane. The influx of Ca2+ can be recorded as store-operated channels (SOC) in the plasma membrane or as a current known as the Ca2+-release-activated current (I(crac)). A critical question in cell signalling is how SOC and I(crac) sense and respond to Ca2+-store depletion: in one model, a messenger molecule is generated that activates Ca2+ entry in response to store depletion; in an alternative model, InsP3 receptors in the stores are coupled to SOC and I(crac). The mammalian Htrp3 protein forms a well defined store-operated channel and so provides a suitable system for studying the effect of Ca2+-store depletion on SOC and I(crac). We show here that Htrp3 channels stably expressed in HEK293 cells are in a tight functional interaction with the InsP3 receptors. Htrp3 channels present in the same plasma membrane patch can be activated by Ca2+ mobilization in intact cells and by InsP3 in excised patches. This activation of Htrp3 by InsP3 is lost on extensive washing of excised patches but is restored by addition of native or recombinant InsP3-bound InsP3 receptors. Our results provide evidence for the coupling hypothesis, in which InsP3 receptors activated by InsP3 interact with SOC and regulate I(crac).

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Calcium / metabolism
  • Calcium Channels / chemistry
  • Calcium Channels / genetics
  • Calcium Channels / metabolism
  • Cattle
  • Cell Line
  • Cell Membrane / metabolism
  • Inositol 1,4,5-Trisphosphate / metabolism*
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ion Channels / agonists
  • Ion Channels / metabolism*
  • Microsomes / metabolism
  • Rats
  • Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • TRPC Cation Channels
  • Thapsigargin / pharmacology


  • Calcium Channels
  • Inositol 1,4,5-Trisphosphate Receptors
  • Ion Channels
  • Receptors, Cytoplasmic and Nuclear
  • Recombinant Proteins
  • TRPC Cation Channels
  • TRPC3 cation channel
  • Thapsigargin
  • Inositol 1,4,5-Trisphosphate
  • Calcium