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

Abstract

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.