Regulations of myo-inositol homeostasis: Mechanisms, implications, and perspectives

Phosphorylation is the most common module of cellular signalling pathways. The dynamic nature of phosphorylation, which is conferred by the balancing acts of kinases and phosphatases, allows this modification to finely control crucial cellular events such as growth, differentiation, and cell cycle progression. Although most research to date has focussed on protein phosphorylation, non-protein phosphorylation substrates also play vital roles in signal transduction. The most well-established substrate of non-protein phosphorylation is inositol, whose phosphorylation generates many important signalling molecules such as the second messenger IP₃, a key factor in calcium signalling. A fundamental question to our understanding of inositol phosphorylation is how the levels of cellular inositol are controlled. While the availability of protein phosphorylation substrates is known to be readily controlled at the levels of transcription, translation, and/or protein degradation, the regulatory mechanisms that control the uptake, synthesis, and removal of inositol are underexplored. Potentially, such mechanisms serve as an important layer of regulation of cellular signal transduction pathways. There are two ways in which mammalian cells acquire inositol. The historic use of radioactive ³H-myo-inositol revealed that inositol is promptly imported from the extracellular environment by three specific symporters SMIT1/2, and HMIT, coupling sodium or proton entry, respectively. Inositol can also be synthesized de novo from glucose-6P, thanks to the enzymatic activity of ISYNA1. Intriguingly, emerging evidence suggests that in mammalian cells, de novo myo-inositol synthesis occurs irrespective of inositol availability in the environment, prompting the question of whether the two sources of inositol go through independent metabolic pathways, thus serving distinct functions. Furthermore, the metabolic stability of myo-inositol, coupled with the uptake and endogenous synthesis, determines that there must be exit pathways to remove this extraordinary sugar from the cells to maintain its homeostasis. This essay aims to review our current knowledge of myo-inositol homeostatic metabolism, since they are critical to the signalling events played by its phosphorylated forms.