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 G(13)alpha 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 G(13), G(q) and G(i) occurs rapidly in neuroblastoma cells, but that stimulation of RhoA is transient whereas the activation of G(q)- and G(i)-mediated pathways is sustained. In addition to G(13)alpha, we demonstrate that G(q)alpha is capable of promoting neurite retraction. G(q)-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 G(s) 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 G(13) and G(q), respectively, and that agonists that activate G(s) inhibit the RhoA-dependent pathway.
Couvillon
Anthony D
AD
Department of Molecular Physiology and Biophysics, 831B Light Hall, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Exton
John H
JH
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D048430:Cell Shape; D005576:Colforsin / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008246:Lysophospholipids / Q000494:pharmacology*; D051379:Mice; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D000067956:Adenylyl Cyclase Inhibitors; D008246:Lysophospholipids; D010726:Phosphodiesterase Inhibitors; D020033:Protein Isoforms; D049368:Receptors, Lysophosphatidic Acid; D011993:Recombinant Fusion Proteins; D005576:Colforsin; D015544:Inositol 1,4,5-Trisphosphate; D020558:GTP Phosphohydrolases; D020962:Heterotrimeric GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein; D000262:Adenylyl Cyclases; C032881:lysophosphatidic acid; D015056:1-Methyl-3-isobutylxanthine; D004121:Dimethyl Sulfoxide