Target-specific PIP₂ signalling: How might it work?

Phosphatidylinositol 4,5-bisphosphate (PIP₂)-mediated signalling is a new and rapidly developing area in the field of cellular signal transduction. With the extensive and growing list of PIP₂-sensitive membrane proteins (many of which are ion channels and transporters) and multiple signals affecting plasma membrane PIP₂ levels, the question arises as to the cellular mechanisms that confer specificity to PIP₂-mediated signalling. In this review we critically consider two major hypotheses for such possible mechanisms: (i) clustering of PIP₂ in membrane microdomains with restricted lateral diffusion, a hypothesis providing a mechanism for spatial segregation of PIP₂ signals and (ii) receptor-specific buffering of the global plasma membrane PIP₂ pool via Ca²⁺-mediated stimulation of PIP₂ synthesis or release, a concept allowing for receptor-specific signalling with free lateral diffusion of PIP₂. We also discuss several other technical and conceptual intricacies of PIP₂-mediated signalling.