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. 2007 Aug 1;582(Pt 3):967-75.
doi: 10.1113/jphysiol.2007.132787. Epub 2007 Apr 5.

Target-specific PIP(2) signalling: how might it work?

Nikita Gamper  1 , Mark S Shapiro
Affiliations

Target-specific PIP(2) signalling: how might it work?

Nikita Gamper et al. J Physiol. .

Abstract

Phosphatidylinositol 4,5-bisphosphate (PIP(2))-mediated signalling is a new and rapidly developing area in the field of cellular signal transduction. With the extensive and growing list of PIP(2)-sensitive membrane proteins (many of which are ion channels and transporters) and multiple signals affecting plasma membrane PIP(2) levels, the question arises as to the cellular mechanisms that confer specificity to PIP(2)-mediated signalling. In this review we critically consider two major hypotheses for such possible mechanisms: (i) clustering of PIP(2) in membrane microdomains with restricted lateral diffusion, a hypothesis providing a mechanism for spatial segregation of PIP(2) signals and (ii) receptor-specific buffering of the global plasma membrane PIP(2) pool via Ca(2+)-mediated stimulation of PIP(2) synthesis or release, a concept allowing for receptor-specific signalling with free lateral diffusion of PIP(2). We also discuss several other technical and conceptual intricacies of PIP(2)-mediated signalling.

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Figures

Figure 1
Figure 1. Schematic representation of two opposing views on the effect of PLC-coupled receptor stimulation on global PIP2 abundance, as discussed in the text
PIP2 molecules within the bilayer are shown as red ovals. On the left is depicted the scenario of restricted PIP2 diffusion, resulting in local PIP2 microdomains. A hypothetical microdomain is shaded grey. Stimulation of the PLC-coupled receptor within the microdomain causes a drop of local [PIP2] without appreciably affecting global membrane PIP2 abundance. In this case, triggering of the receptor only affects spatially co-localized channels. Depicted on the right is the opposing scenario in which free lateral diffusion of PIP2 is permitted within the entire membrane area. Strong stimulation of PLC-coupled receptors in this case depletes [PIP2] globally, affecting all PIP2-sensitive membrane targets. L, ligand of the Gq/11-coupled receptor; PLC, phospholipase C.
Figure 2
Figure 2. Depiction of how channels isolated in the patch of membrane in the cell-attached pipette can be inhibited within the context of PIP2 as a diffusible messenger
PIP2 molecules within the bilayer are shown as red ovals. We assume that neither ligand-bound receptors nor activated PLC can diffuse through the membrane into the pipette tip, an assumption supported by previous work (Soejima & Noma, 1984). Stimulation of Gq/11-coupled receptors in the membrane outside of the patch results in global lowering of [PIP2], a gradient of [PIP2] between the membrane patch and the membrane outside of the patch, diffusion of PIP2 from the patch to the rest of the cell membrane, lowered [PIP2] in the membrane patch, and unbinding of PIP2 from the channel, resulting in its inhibition. Note that such a result is predicated on free diffusion of PIP2 within the lipid bilayer. L, ligand of the Gq/11-coupled receptor; PLC, phospholipase C.
Figure 3
Figure 3. ‘Buffering’ of global plasma membrane PIP2 pool
Hypothesis of ‘buffering’ of global plasma membrane PIP2 pool by concurrent stimulation of PIP2 hydrolysis and PIP2 synthesis (or release from locally sequestered PIP2 domains, such as proposed MARCKS–PIP2 clusters) by those PLC-coupled receptors that induce Ca2+ transients (such as bradykinin B2 and purinergic P2Y receptors in SCG neurons). See text for details. L, ligand of the Gq/11-coupled receptor; PLC, phospholipase C; ER, endoplasmatic reticulum; IP3, inositol 1,4,5-trisphosphate.
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