Transmembrane communication and disease.

Many disease affect cell behaviour by an effect at the cell surface, often leading to altered communication across the plasma membrane. Two examples of this from our own work are presented. The first concerns the induction of pores, leading to a breach of insulating properties of the cell membrane, by agents as diverse as certain viruses, bacterial and animal toxins, or immune molecules. In each case, membrane damage can be prevented by divalent cations such as Ca2+ or Zn2+. The second example concerns the effect of stress stimuli on the ability of cells to take up glucose. Different stresses, such as hyperthermia, toxic chemicals or infection by certain viruses, cause cells to increase glucose uptake. As with insulin-stimulated glucose uptake, the mechanism is by translocation of the glucose transporter protein from an intracellular (inactive) site to the plasma membrane.

Ca2+ and the interaction of pore-formers with membranes.

The interaction of pore-forming agents, such as Sendai virus, influenza virus (at pH 5 3), activated complement, Staphylococcus aureus α-toxin, melittin and polylysine, with the surface membrane of cells has been studied. In each case the following changes are initiated: collapse of membrane potential, leakage of ions, and leakage of phosphorylated metabolites. The changes can be inihibited by extracellular Ca2+ at physiological concentration; Mg2+ is less effective, and Zn2+ is more effective, than Ca2+ Ca2+ appears to act at a stage subsequent to the binding of pore-forming agent to cells. It is concluded that divalent cations are able to protect cells against the damaging effects of certain viruses, toxins or the components of activated complement in a manner that is worthy of further investigation.

How viruses damage cells: alterations in plasma membrane function.

The effect of viruses on plasma membrane function has been studied in two types of situation: (i) during the toxin-like action of paramyxoviruses when fusing with susceptible cells, and (ii) during an infectious cycle initiated by different viruses in various cell types. The nature of the permeability changes induced during the toxin-like action of viruses, and its modulation by extra-cellular Ca2+, are described: membrane potential collapses, intracellular ions and metabolites leak out of, and extracellular ions leak into cells, but lysis does not take place. The biological significance of such changes, and their relation to changes induced by other pore-forming agents, are discussed. Changes in membrane permeability such as those mentioned above have not been detected during infection of cultured cells by paramyxo (Sendai, measles, mumps), orthomyxo (influenza), rhabdo (vesicular stomatitis), toga (Semliki Forest) or herpes viruses. On the contrary, sugar uptake is increased when BHK cells are infected with vesicular stomatitis virus, semliki forest virus or herpes virus. Cultured neurones infected with herpes simplex virus show changes in electrical activity. The pathophysiological significance of these alterations in membrane function, which occur in viable cells, is discussed. It is concluded that clinical symptoms may result from cell damage caused by virally induced alterations of plasma membrane function in otherwise intact cells.