PT  - JOURNAL ARTICLE
AU  - D L Nunn
AU  - C W Taylor
TI  - Luminal Ca2+ increases the sensitivity of Ca2+ stores to inositol 1,4,5-trisphosphate.
DP  - 1992 Jan 01
TA  - Molecular Pharmacology
PG  - 115--119
VI  - 41
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/41/1/115.short
4100  - http://molpharm.aspetjournals.org/content/41/1/115.full
SO  - Mol Pharmacol1992 Jan 01; 41
AB  - Ca2+ within intracellular stores has been proposed to act with cytosolic inositol 1,4,5-trisphosphate (InsP3) to cause opening of the integral Ca2+ channel of the InsP3 receptor, leading to mobilization of intracellular Ca2+ stores [FEBS Lett. 263:5-9 (1990)]. We have tested that suggestion in saponin-permeabilized rat hepatocytes by manipulating the Ca2+ content of the stores and then determining their sensitivity to InsP3, while keeping the cytosolic Ca2+ concentration constant. Stores depleted of Ca2+ by incubation with ionomycin were significantly less sensitive to InsP3, an effect thought likely to result from the decrease in luminal free Ca2+ concentration rather than from direct effects of ionomycin on InsP3 binding or Ca2+ permeability. The luminal free Ca2+ concentration of stores loaded in the presence of pyrophosphate appeared to be substantially reduced, and again there was a significant inverse correlation between the estimated free Ca2+ concentration of the stores and their sensitivity to InsP3. By following the kinetics of 45Ca2+ uptake into empty stores in the presence of inositol trisphosphorothioate, a stable InsP3 analogue, we demonstrated that stores respond to inositol trisphosphorothioate only after their luminal free Ca2+ concentration exceeds a critical level. We conclude that InsP3 and luminal Ca2+ together regulate Ca2+ mobilization from intracellular stores, and we discuss some of the implications of this interaction for the complex Ca2+ signals evoked by extracellular stimuli.