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

Cell Signal. 2010 Jul;22(7):1153-61. doi: 10.1016/j.cellsig.2010.03.010. Epub 2010 Mar 19.


Among phospholipase C (PLC) isozymes (beta, gamma, delta, epsilon, zeta and eta), PLC-beta plays a key role in G-protein coupled receptor (GPCR)-mediated signaling. PLC-beta 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-beta subtype to GPCRs, and explored the molecular mechanism underlying the specificity. Firstly, we found that PLC-beta1 and PLC-beta 3 are activated by bradykinin (BK) or lysophosphatidic acid (LPA), respectively. BK-triggered phosphoinositides hydrolysis and subsequent Ca(2+) mobilization were abolished specifically by PLC-beta1 silencing, whereas LPA-triggered events were by PLC-beta 3 silencing. Secondly, we showed the evidence that PDZ scaffold proteins is a key mediator for the selective coupling between PLC-beta subtype and GPCR. We found PAR-3 mediates physical interaction between PLC-beta1 and BK receptor, while NHERF2 does between PLC-beta 3 and LPA(2) 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-beta is selectively coupled to GPCR via PDZ scaffold proteins in given cell types and plays differential role in the signaling of various GPCRs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Bradykinin / metabolism
  • Bradykinin / pharmacology*
  • Calcium / metabolism
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation / drug effects
  • Gene Knockdown Techniques
  • HeLa Cells
  • Humans
  • Lysophospholipids / metabolism
  • Lysophospholipids / pharmacology*
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism*
  • PDZ Domains
  • Phospholipase C beta / antagonists & inhibitors
  • Phospholipase C beta / metabolism*
  • Phospholipase C beta / physiology
  • Phosphoproteins / chemistry
  • Phosphoproteins / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects
  • Sodium-Hydrogen Exchangers / chemistry
  • Sodium-Hydrogen Exchangers / metabolism*


  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Lysophospholipids
  • Membrane Proteins
  • PARD3 protein, human
  • Phosphoproteins
  • Receptors, G-Protein-Coupled
  • Sodium-Hydrogen Exchangers
  • sodium-hydrogen exchanger regulatory factor
  • PLCB1 protein, human
  • PLCB3 protein, human
  • Phospholipase C beta
  • lysophosphatidic acid
  • Bradykinin
  • Calcium