Calcium: its modulation in liver by cross-talk between the actions of glucagon and calcium-mobilizing agonists

Abstract

a vital physiological event from the very beginning of life at the moment of fertilization, to its very end at the final beat of the heart. These changes are brought about either as a result of mobilizing intracellular Ca2+ or as a result of inflow of the ion from the extracellular medium. The means by which cells control Ca2+ fluxes, and particularly Ca21 inflow, is increasingly becoming a focus of attention. Changes in intracellular [Ca2+], especially that following Ca2+ inflow across the cell membrane induced by a range of different stimuli, are the trigger not only in the shortterm but also in the long-term of many vital physiological responses in cells in a range of tissues and species. Moreover, aberrant control of Ca2+ fluxes appears to be associated with many pathological situations. During the past decade in particular, a large number of articles have been published about many aspects of cellular Ca2+ fluxes: about the discovery and generation of the new second messenger Ins(1,4,5)P3 and of the related enzymic reactions that generate and dispose of it; about the range of agonists able to induce changes in cellular Ca2+ fluxes; about the cellular compartments that appear to contain agonist-sensitive Ca2+ pools; about the continual development of new techniques to measure and locate the ion within cells; and about how 'cross-talk' between second messenger systems, such as those generating cyclic AMP and Ins(1,4,5)P3 for instance, are able to induce/modulate Ca2+ fluxes. Numerous offerings and ideas have in turn evolved from these studies as to the nature of the mechanisms involved in the control of cell Ca2+. The aim of this article is to contribute further to this knowledge by integrating a number of relevant observations and reports obtained over the years by numerous investigators and to synthesize a general scheme that we hope will be useful in the current debates about the control of cellular Ca2+ fluxes. We focus on liver tissue, drawing upon the large body of information available about such fluxes derived from studies from both single cells (hepatocytes) and the intact organ (perfused liver). We also focus particularly on the issue of how glucagon (and cyclic AMP) might regulate/modulate Ca2+ fluxes induced by calcium-mobilizing agonists. This is an aspect of the control of Ca2+ fluxes in liver that is not only important in many aspects of liver function, but also one that we believe holds clues