The mechanism of alpha-adrenergic agonist action in liver.

Abstract

Summary1. Although the mechanism of action of a‐adrenergic agonists in liver tissue is somewhat complex, a number of experimental approaches can be usefully employed to identify the molecular details of the events that occur.2. Receptors specific for α1‐adrenergic agonists located on the plasma membranes of rat liver cells have been partially characterized using pharmacological agents, affinity labels and monoclonal antibodies. Much of this work has employed isolated plasma membrane fractions and does not take account of tissue‐related factors which may now be studied in the intact perfused rat liver, following the development of an appropriate assay system.3. Because a redistribution of cellular Ca2+ is central to the mechanism of action of a‐adrenergic agonists in liver, it is important to first gain an understanding of basic cellular Ca2+ regulation. Knowledge about the compartmentation of cellular calcium and about Ca2+‐translocation systems located in the mitochondria, plasma membrane and endoplasmic reticulum is now quite extensive. However, the role of mitochondria in the regulation of intracellular Ca2+ is still unclear; it now appears that the mitochondrial calcium content is much less than considered previously. This may have important implications for such a regulatory role.4. The sequence of Ca2+ movements that may occur when a‐adrenergic agonists interact with liver have been identified and are as follows: (a) Ca2+ is mobilized from an intracellular pool(s) (mitochondria plus endoplasmic reticulum and/or plasma membranes). (b) This elevates the cytoplasmic free Ca2+ concentration and leads to an efflux of the ion from the cell. (c) At this time, Ca2+‐sensitive metabolic events in the cytoplasm are activated and an increase in Ca2+‐cycling occurs across the plasma membrane. (d) Immediately after the hormone is withdrawn, there is a net influx of Ca2+ into the cell, and the intracellular Ca2+ pools and transmembrane fluxes are restored to the pre‐induced states. In this model, Ca2+ movements across the plasma membrane play a key role in regulating the cytoplasmic Ca2+ concentration.5. In the perfused rat liver it has been possible to define in quite precise terms the amounts and rates of Ca2+ mobilized in each of these stages.6. Although several proposals for ‘second messengers’ to link the hormone‐receptor interaction with initial Ca2+ mobilization have been made, at this time only polyphosphoinositide turnover appears to be a suitable candidate.