Dual mechanisms of Ca²⁺ oscillations in hepatocytes

Calcium (Ca²⁺) oscillations in hepatocytes control many critical cellular functions, including glucose metabolism and bile secretion. The mechanisms underlying repetitive Ca²⁺ oscillations and how these mechanisms regulate these oscillations is not fully understood. Recent experimental evidence has shown that both Ca²⁺ regulation of the inositol 1,4,5-trisphosphate (IP₃) receptor and IP₃ metabolism generate Ca²⁺ oscillations and co-exist in hepatocytes. To investigate the effects of these feedback mechanisms on the Ca²⁺ response, we construct a mathematical model of the Ca²⁺ signalling network in hepatocytes. The model accounts for the biphasic regulation of Ca²⁺ on the IP₃ receptor (IP₃R) and the positive feedback from Ca²⁺ on IP₃ metabolism, via activation of phospholipase C (PLC) by agonist and Ca²⁺. Model simulations show that Ca²⁺ oscillations exist for both constant [IP₃] and for [IP₃] changing dynamically. We show, both experimentally and in the model, that as agonist concentration increases, Ca²⁺ oscillations transition between simple narrow-spike oscillations and complex broad-spike oscillations. The model predicts that narrow-spike oscillations persist when Ca²⁺ 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 Ca²⁺ oscillations in hepatocytes.