Dual mechanisms of Ca oscillations in hepatocytes.

Calcium (Ca) oscillations in hepatocytes control many critical cellular functions, including glucose metabolism and bile secretion. The mechanisms underlying repetitive Ca oscillations and how these mechanisms regulate these oscillations is not fully understood. Recent experimental evidence has shown that both Ca regulation of the inositol 1,4,5-trisphosphate (IP) receptor and IP metabolism generate Ca oscillations and co-exist in hepatocytes. To investigate the effects of these feedback mechanisms on the Ca response, we construct a mathematical model of the Ca signalling network in hepatocytes. The model accounts for the biphasic regulation of Ca on the IP receptor (IPR) and the positive feedback from Ca on IP metabolism, via activation of phospholipase C (PLC) by agonist and Ca. Model simulations show that Ca oscillations exist for both constant [IP] and for [IP] changing dynamically. We show, both experimentally and in the model, that as agonist concentration increases, Ca oscillations transition between simple narrow-spike oscillations and complex broad-spike oscillations. The model predicts that narrow-spike oscillations persist when Ca transport across the plasma membrane is blocked. This prediction has been experimentally validated. In contrast, broad-spike oscillations are terminated when plasma membrane transport is blocked. We conclude that multiple feedback mechanisms participate in regulating Ca oscillations in hepatocytes.

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