Lysophosphatidylinositol causes neurite retraction via GPR55, G13 and RhoA in PC12 cells

PLoS One. 2011;6(8):e24284. doi: 10.1371/journal.pone.0024284. Epub 2011 Aug 31.


GPR55 was recently identified as a putative receptor for certain cannabinoids, and lysophosphatidylinositol (LPI). Recently, the role of cannabinoids as GPR55 agonists has been disputed by a number of reports, in part, because studies investigating GPR55 often utilized overexpression systems, such as the GPR55-overexpressing HEK293 cells, which make it difficult to deduce the physiological role of endogenous GPR55. In the present study, we found that PC12 cells, a neural model cell line, express endogenous GPR55, and by using these cells, we were able to examine the role of endogenous GPR55. Although GPR55 mRNA and protein were expressed in PC12 cells, neither CB(1) nor CB(2) mRNA was expressed in these cells. GPR55 was predominantly localized on the plasma membrane in undifferentiated PC12 cells. However, GPR55 was also localized in the growth cones or the ruffled border in differentiated PC12 cells, suggesting a potential role for GPR55 in the regulation of neurite elongation. LPI increased intracellular Ca(2+) concentration and RhoA activity, and induced ERK1/2 phosphorylation, whereas endogenous and synthetic cannabinoids did not, thereby suggesting that cannabinoids are not GPR55 agonists. LPI also caused neurite retraction in a time-dependent manner accompanied by the loss of neurofilament light chain and redistribution of actin in PC12 cells differentiated by NGF. This LPI-induced neurite retraction was found to be G(q)-independent and G(13)-dependent. Furthermore, inactivation of RhoA function via C3 toxin and GPR55 siRNA knockdown prevented LPI-induced neurite retraction. These results suggest that LPI, and not cannabinoids, causes neurite retraction in differentiated PC12 cells via a GPR55, G(13) and RhoA signaling pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • GTP-Binding Protein alpha Subunits, G12-G13 / genetics
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism*
  • Lysophospholipids / pharmacology*
  • Neurites / drug effects*
  • Neurites / metabolism*
  • PC12 Cells
  • Rats
  • Receptors, Cannabinoid / genetics
  • Receptors, Cannabinoid / metabolism*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*


  • GPR55 protein, rat
  • Lysophospholipids
  • Receptors, Cannabinoid
  • Receptors, G-Protein-Coupled
  • lysophosphatidylinositol
  • GTP-Binding Protein alpha Subunits, G12-G13
  • rhoA GTP-Binding Protein