Model of intercellular calcium oscillations in hepatocytes: synchronization of heterogeneous cells

Abstract

Hepatocytes respond with repetitive cytosolic calcium spikes to stimulation by vasopressin and noradrenalin. In the intact liver, calcium oscillations occur in a synchronized fashion as periodic waves across whole liver lobules, but the mechanism of intercellular coupling remains unclear. Recently, it has been shown that individual hepatocytes can have very different intrinsic oscillation frequencies but become phase-locked when coupled by gap junctions. We investigate the gap junction hypothesis for intercellular synchronization by means of a mathematical model. It is shown that junctional calcium fluxes are effective in synchronizing calcium oscillations in coupled hepatocytes. An experimentally testable estimate is given for the junctional coupling coefficient required; it mainly depends on the degree of heterogeneity between cells. Intercellular synchronization by junctional calcium diffusion may occur also in other cell types exhibiting calcium-activated calcium release through InsP(3) receptors, if the gap junctional coupling is strong enough and the InsP(3) receptors are sufficiently sensitized by InsP(3).