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

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.

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 G_q/11-coupled receptor; PLC, phospholipase C.

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 G_q/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 G_q/11-coupled receptor; PLC, phospholipase C.

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.