Evidence of sinks and sources in the PLC activated PIP 2 cycle

Abstract In many eukaryotic signalling cascades, receptor mediated phospholipase C (PLC) activity triggers phosphatidylinositol 4,5 bisphosphate (PIP 2 ) hydrolysis leading to information transfer in cells. Coupled with PLC activation is a sequence of reactions spread across multiple compartments by which PIP 2 is resynthesized, a process essential to maintain PIP 2 levels and support sustained PLC signalling. The biochemical strategies to co-ordinate these reactions and support PIP 2 levels have remained poorly understood. In particular, the question of whether the PIP 2 cycle is a closed cycle with no net addition or loss of metabolites has not been addressed. Using mathematical modelling approaches, we find that a closed PIP 2 cycle cannot explain experimentally observed changes in the metabolic intermediates when changing enzyme activities in the PIP 2 cycle. Thus, we propose that the PIP 2 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.