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.
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