Subtype-specific role of phospholipase C-β in bradykinin and LPA signaling through differential binding of different PDZ scaffold proteins

Among phospholipase C (PLC) isozymes (β, γ, δ, ε, ζ and η), PLC-β plays a key role in G-protein coupled receptor (GPCR)-mediated signaling. PLC-β subtypes are often overlapped in their distribution, but have unique knock-out phenotypes in organism, suggesting that each subtype may have the different role even within the same type of cells. In this study, we examined the possibility of the differential coupling of each PLC-β subtype to GPCRs, and explored the molecular mechanism underlying the specificity. Firstly, we found that PLC-β1 and PLC-β3 are activated by bradykinin (BK) or lysophosphatidic acid (LPA), respectively. BK-triggered phosphoinositides hydrolysis and subsequent Ca²⁺ mobilization were abolished specifically by PLC-β1 silencing, whereas LPA-triggered events were by PLC-β3 silencing. Secondly, we showed the evidence that PDZ scaffold proteins is a key mediator for the selective coupling between PLC-β subtype and GPCR. We found PAR-3 mediates physical interaction between PLC-β1 and BK receptor, while NHERF2 does between PLC-β3 and LPA₂ receptor. Consistently, the silencing of PAR-3 or NHERF2 blunted PLC signaling induced by BK or LPA respectively. Taken together, these data suggest that each subtype of PLC-β is selectively coupled to GPCR via PDZ scaffold proteins in given cell types and plays differential role in the signaling of various GPCRs.