Lysophosphatidic acid and thrombin receptors require both Gα12 and Gα13 to regulate axonal morphology in hippocampal neurons

Abstract

The Gα subunits of the G12 family of heterotrimeric guanine nucleotide-binding proteins (G proteins), defined by Gα12 and Gα13, have many cellular functions in common, including stimulation of stress fiber formation and focal adhesion assembly via the small GTPase RhoA activation. We and others previously showed that Gα12 and Gα13 mediate neurite retraction in neuronal cell lines, but their roles in primary cultured neurons have not been adequately understood. Here, we found that expression of constitutively active mutants of Gα12 or Gα13 caused growth cone collapse dependent on Rho-kinase activity in hippocampal neurons. The stimulation of thrombin and lysophosphatidic acid (LPA) receptors, which have been thought to selectively couple to Gα12 and Gα13, respectively, caused growth cone collapse and suppressed axon branching dependent on Rho-kinase activity in hippocampal neurons. Thrombin- and LPA-induced growth cone collapse was suppressed by both single knockdown of Gα12 and Gα13 with short hairpin RNAs and this suppression was augmented by double knockdown of both Gα12 and Gα13. These results suggest that thrombin and LPA receptors couple to both Gα12 and Gα13 for growth cone collapse. © 2008 Pharmaceutical Society of Japan.