How do inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate regulate intracellular Ca2+?

The original proposal of Berridge (1983), that inositol 1,4,5trisphosphate [Ins( 1,4,5)P,] is the second messenger linking receptor-activated phosphoinositide turnover with intracellular Ca2+ mobilization, has been well supported by many experiments (Streb et al., 1983; Berridge & Irvine, 1984; Berridge, 1987). However, more recent evidence has suggested that this proposal may need some qualification; specifically, it is emerging that Ins( 1,4,5)P, is a messenger, not the messenger, and that its essential partner in a ‘duet’ in Ca2+ regulation is inositol 1,3,4,5-tetrakisphosphate [Ins( 1,3,4,5)P,] (Irvine et al., 1988). 1ns(1,3,4,5)P4 (Batty et a/., 1985), is formed by a 3-phosphorylation of Ins( 1,4,5)P, (Irvine et al., 1986; Hawkins et al., 1986; Hansen et al., 1986; Stewart et al., 1986; Biden & Wollheim, 1986) and is degraded by a 5-dephosphorylation (Batty etal., 1985; Hawkins etal., 1986) to form Ins( 1,3,4)P, (Irvine et a/., 1984). It is produced rapidly on cell stimulation, with kinetics very similar to Ins(1,4,5)P, (e.g. Batty et al., 1985; Hawkins etal., 1986; Hansen etal., 1986; Biden & Wollheim, 1986). The regulation of Ins( 1,4,5)P3-3-kinase by Ca2+, and possibly by other factors, was reviewed recently by Irvine et al. (1988) and that discussion will not be reiterated here. The only additional point worth noting is that, it has been suggested that there is some indirect evidence for the existence of a membrane-bound, receptor-regulated Ins( 1,4,5)P3-3-kinase in some tissues (Irvine et al., 1988). If that is true, then the recent observation of transient production in stimulated neutrophils of a phosphatidylinositol trisphosphate (PtdInsP,) (Traynor-Kaplan et al., 1988), could be due to such an activated membrane-bound Ins( 1,4,5)P,kinase using phosphatidyl 4,5-bisphosphate [PtdIns(4,5)P2] as a substrate, until sufficient levels are reached of its true substrate [Ins( 1,4,5)P,]. This thought in turn inspires the rather enticing question, is the recently reported Ptdlns3-kinase (Whitman et al., 1988) also due to the same enzyme? lrvine et al. (1988) have summarized the evidence that Ins( 1,3,4,5)P, aids and abets Ins( 1,4,5)P3 in controlling Ca2+. In the original proposal we drew distinct lines of demarcation in so far as we suggested that Ins( 1,4,5)P3 controlled intracellular mobilization, and that Ins( 1 ,3,4,5)P4 controlled Ca2+ entry (Irvine & Moor, 1986). However, since the publication of this idea, the lines have become blurred, and it has been more recently suggested (Irvine et al., 1988) that the synergism between Ins(1,4,5)P3 and Ins( 1,3,4,5)P4 might extend, at least in some tissues, to include intracellular mobilization of Ca2+ as well as entry of Ca2 + from outside the cell (see below). What might be the mechanism of this synergism, and what might be the reason for it? In the original proposal of Berridge (1983) and Streb et al. (1983), there was no need to invoke any help from Ins( 1,3,4,5)P4 (which was undreamt of at that time anyway). In most permeabilized cell preparations, Ins( 1,3,4,5)P, has little effect. Furthermore, the hypothesis of Putney (1986) (which received considerable support from Merritt & Rink, 1987), in which a mechanism was pro-