The interaction of lithium ions with inositol lipid signalling systems.

Abstract

There is now a growing consensus that hormones and neurotransmitters, in stimulating or inhibiting cellular function, produce their characteristic changes by utilizing a relatively small number of general receptor transduction systems. One such mechanism, which was initially conceived to have as its end-point, the elevation in cytosolic free Ca*+, is the inositol lipid signalling system. This activation process is now known, in addition, to lead to the activation of protein kinase C, and there is a large body of evidence indicating that the synergistic action of Ca’+ and protein kinase C plays a central role in controlling cell function (for a recent review see Downes & Michell, 1985). Despite the enormous advances that this decade has brought in our understanding of the mechanisms by which receptor agonists increase the cytosolic free Ca2+ concentration and activate cellular protein kinases, our ability to perturb these processes pharmacologically, other than at the level of the receptor itself, has remained somewhat primitive. The ready availability of specific pharmacological research tools would do much to speed our understanding both of the extent to which the signalling system pervades general cell function, and of the detailed control processes which govern the performance of the inositol lipid cycle under conditions of both shortand long-term receptor stimulation. Also, at a time when the long-held notion that second messenger systems are too ubiquitous to be plausible drug targets is receiving at least a partial come-uppance with the advent of tissue-selective cyclic nucleotide phosphodiesterase inhibitors, i t does not seem too fanciful to advance the hope that the inositol lipid cycle and its sequelae might similarily yield potentially valuable therapeutic agents. I t is from this perspective that the present short review is written. One of the few agents that interferes with the inositol lipid cycle in any selective sense is lithium. This agent, in the form of lithium carbonate, has been used for over a quarter of a century in the treatment of manic-depressive illness. Its utility is proven (Schou, 1976), but its mode of action remains a matter of conjecture. Throughout the 1970s, Allison and his colleagues conducted an investigation into the interaction of lithium with inositol metabolism, primarily in the central nervous system (CNS). The brain of animals receiving lithium (and with plasma lithium levels in the