Role of heterotrimeric G-proteins in lysophosphatidic acid-mediated neurite retraction by RhoA-dependent and -independent mechanisms in N1E-115 cells

In neuronal cells, current evidence suggests that G13α and RhoA play significant roles in LPA-mediated neurite retraction; however, the contribution of other G-proteins to this process is less well-understood. We provide evidence that LPA activation of G13, Gq and Gi occurs rapidly in neuroblastoma cells, but that stimulation of RhoA is transient whereas the activation of Gq- and Gi-mediated pathways is sustained. In addition to G13α, we demonstrate that Gqα is capable of promoting neurite retraction. Gq-mediated retraction is RhoA-independent and is likely mediated via a mechanism involving protein kinase C and calcium flux. Additionally, we provide evidence that activation of adenylyl cyclase via Gs inhibits RhoA-mediated neurite retraction via protein kinase A-mediated inhibition of RhoA action. Taken together, we hypothesize that LPA promotes neurite retraction via RhoA-dependent and -independent pathways involving G13 and Gq, respectively, and that agonists that activate Gs inhibit the RhoA-dependent pathway.