A novel Ca super(2+)-induced Ca super(2+) release mechanism mediated by neither inositol trisphosphate nor ryanodine receptors

• Published in: Biochemical journal 2002-02, Vol.361 (3), p.605-611
• Main Authors: Wissing, F, Nerou, E P, Taylor, C W
• Format: Article
• Language: English
• ISSN: 0264-6021

Members of both major families of intracellular Ca super(2+) channels, ryanodine and inositol 1,4,5-trisphosphate (IP sub(3)) receptors, are stimulated by substantial increases in cytosolic free Ca super(2+) concentration ([Ca super(2+)] sub(c)). They thereby mediate Ca super(2+)-induced Ca super(2+) release (CICR), which allows amplification and regenerative propagation of intracellular Ca super(2+) signals. In permeabilized hepatocytes, increasing [Ca super(2+)] sub(c) to 10 mu M stimulated release of 30 plus or minus 1% of the intracellular stores within 60s; the EC sub(50) occurred with a free [Ca super(2+)] of 170 plus or minus 29nM. This CICR was abolished at 2 degree C. The same fraction of the stores was released by CICR before and after depletion of the IP sub(3)-sensitive stores, and CICR was not blocked by antagonists of IP sub(3) receptors. Ryanodine, Ruthenium Red and tetracaine affected neither the Ca super(2+) content of the stores nor the CICR response. Sr super(2+) and Ba super(2+) (EC sub(50) = 166nM and 28 mu M respectively) mimicked the effects of increased [Ca super(2+)] on the intracellular stores, but Ni super(2+) blocked the passive leak of Ca super(2+) without blocking CICR. In rapid superfusion experiments, maximal concentrations of IP sub(3) or Ca super(2+) stimulated Ca super(2+) release within 80ms. The response to IP sub(3) was complete within 2s, but CICR continued for tens of seconds despite a slow [half-time (t sub( one half )) = 3.54 plus or minus 0.07 s] partial inactivation. CICR reversed rapidly (t sub( one half ) = 529 plus or minus 17 ms) and completely when the [Ca super(2+)] was reduced. We conclude that hepatocytes express a novel temperature-sensitive, ATP-independent CICR mechanism that is reversibly activated by modest increases in [Ca super(2+)], and does not require IP sub(3) or ryanodine receptors or reversal of the sarcoplasmic/endoplasmic-reticulum Ca super(2+)-ATPase. This mechanism may both regulate the Ca super(2+) content of the intracellular stores of unstimulated cells and allow even small intracellular Ca super(2+) signals to be amplified by CICR.