Evidence of sinks and sources in the phospholipase C-activated PIP₂ cycle.

In many eukaryotic signalling cascades, receptor-mediated phospholipase C (PLC) activity triggers phosphatidylinositol-4,5-bisphosphate (PIP₂ ) hydrolysis, leading to information transfer. Coupled with PLC activation is a sequence of reactions spread across multiple compartments which resynthesize PIP₂ , a process essential for supporting sustained PLC signalling. The biochemical strategies coordinating these reactions and, in particular, whether this is a closed cycle with no net addition or loss of metabolites, are poorly understood. Using mathematical models, we find that most closed PIP₂ cycles cannot explain experimentally observed changes in key metabolic intermediates in particular mutants. Thus, we propose that the PIP₂ cycle likely includes at least one metabolic source and one sink whose net activity results in the experimentally observed regulation of this key signalling pathway.

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