Dual mechanisms of Ca2+ oscillations in hepatocytes

Ielyaas Cloete, Paula J. Bartlett, Vivien Kirk, Andrew P. Thomas, James Sneyd

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article number110390
JournalJournal of Theoretical Biology
Volume503
DOIs
StatePublished - Oct 21 2020

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Applied Mathematics
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Statistics and Probability
  • Modeling and Simulation

Keywords

  • IP
  • IP receptors
  • Models of calcium oscillations
  • Signal transduction

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