Depletion of InsP₃ stores activates a Ca²⁺ and K⁺ current by means of a phosphatase and a diffusible messenger

Abstract

IN non-excitable cells, release of Ca²⁺ from the inositol 1,4,5-trisphosphate (InsP₃)-sensitive store can activate Ca²⁺ entry^1–3. Very little is known about the signal mechanism relating store emptying to plasma membrane Ca²⁺ influx. It has been suggested that the signal may be either a diffusible messenger like an inositol phosphate⁴, or the InsP₃ receptor itself, which, by physically coupling to some component of Ca²⁺ entry in the plasma membrane, may link store release to Ca²⁺ entry⁵. The nature of the Ca²⁺ entry pathway is also unclear. Only in mast cells has a very selective Ca²⁺ current been observed after store emptying⁶. Activation of exogenous 5-hydroxytryptamine (5-HT) receptors expressed in Xenopus oocytes or direct injection of InsP₃ evokes Ca²⁺ entry activated by InsP³ pool depletion⁷. Here we investigate the nature of this influx pathway and find a current activated by pool depletion. This has an unusual selectivity in that it is more permeable to Ca²⁺ ions than to other divalent cations (Ba²⁺, Sr²⁺ or Mn²⁺ ). Moreover, a ^K+ permeability is also stimulated after pool depletion. The activation of this store depletion current involves both a phosphatase and an unidentified diffusible messenger. Both the Ca²⁺ entry pathway and the activating factors found here may be relevant to pool-depleted Ca²⁺ entry in a variety of non-excitable cells.