Inositol tetrakisphosphate as a second messenger: Confusions, contradictions, and a potential resolution

Abstract

The second messenger function of inositol 1,4,5-trisphosphate (InsP3) is now well-defined--it mobilizes Ca2+ from intracellular stores so that cystolic Ca2+ increases. However, the function of inositol 1,3,4,5-tetrakisphosphate (InsP4) has proved much more difficult to fathom, as it has been reported to exert a wide variety of effects in a collection of experimental systems. In this review, a proposed molecular mechanism for InsP4's actions is discussed; it is suggested that InsP4 is the second messenger that controls Ca2+ entry into cells, and that it does so by binding to a receptor which itself interacts, directly or indirectly, with the receptor for InsP3. It is proposed that this is InsP4's true physiological function, but the mechanism by which it exerts this function has led to confusing data concerning its action, and also to some misconceptions about how inositol phosphates control Ca2+ entry.

The effect of inositol 1,3,4,5-tetrakisphosphate on inositol trisphosphate-induced Ca2+ mobilization in freshly isolated and cultured mouse lacrimal acinar cells

“…It has for a long time been evident that mouse lacrimal acinar cells, specifically when freshly isolated, are something of a ' freak ' preparation in which the effects of InsP % are so pronounced as to be clearly obvious. Furthermore, it is also clear that this is not the case in most other experimental systems [1,2]. However, the clear isomeric specificity of the requirement for InsP % [4] has always argued [28] for this being a quantitative rather than a qualitative artefact ; in short, an exaggeration of a physiological event rather than a creation of an entirely new one.…”

“…% has had a long and chequered history as an intracellular second messenger [1,2] surrounded by controversy fuelled by confusing and contradictory results. Overall, InsP % has been shown to influence the kinetics of Ca# + release from stores and Ca# + entry stimulated by InsP $ .…”

“…Overall, InsP % has been shown to influence the kinetics of Ca# + release from stores and Ca# + entry stimulated by InsP $ . However, the effects of InsP % are highly variable between tissues and are undetectable in some systems [1,2]. Some of the most convincing and clear-cut evidence in favour of a role for InsP % as a second messenger has been obtained by measuring the amplification of the InsP $ -induced Ca# + -dependent K + current in mouse lacrimal acinar cells [3][4][5].…”

“…Although not explicitly stated in [6], these data were obtained from cells maintained in primary Abbreviations used : ACh, acetylcholine ; [Ca 2 + ] i , cytosolic free Ca 2 + activity ; fura-2/AM, fura-2 acetoxymethyl ester. 1 To whom correspondence should be sent (e-mail petesmif!liv.ac.uk).…”

Myo‐inositol 1,3,4,5‐tetrakisphosphate can independently mobilise intracellular calcium, via the inositol 1,4,5‐trisphosphate receptor: studies with myo‐inositol 1,4,5‐trisphosphate‐3‐phosphorothioate and myo‐inositol hexakisphosphate

“…Considerable controversy exists as to whether Ins(1,3,4,5)P, possesses an independent or accessory second messenger role. Some evidence suggests that Ins (l,3,4,5)P~ may modulate in calcium entry across the plasma membrane (reviewed [4][5][6]), indeed Ins( 1,3,4,5)P,-activated Ca2' channels have been recently identified in the plasma membrane of endothelial cells [7] and Ins(1,3,4,5)P,-activated Ca2+ mobilisation has been observed using crude microsomes and enriched vesicular plasma membranes prepared from T-lymphocyte and monocyte cell lines [8].…”