G alpha(13) mediates activation of a depolarizing chloride current that accompanies RhoA activation in both neuronal and nonneuronal cells

Loss of membrane potential (membrane depolarization) is one of the earliest and most striking responses of quiescent cells to stimulation with serum o r G protein-coupled receptor (GPCR) agonists such as lysophosphatidic acid and thrombin [1-3], Membrane depolarization is due to the activation of a c hloride conductance [3]. While this response has received relatively little attention in the past, it is clear that the acute loss of membrane potenti al may have important physiological consequences [4-6]. However, the dissec tion of the underlying G protein pathway and the establishment of cause-eff ect relationships have remained elusive to date. Here we report that, in ne uronal cells, the depolarizing chloride current invariably accompanies GPCR -induced activation of RhoA and subsequent neurite retraction, and neither of these events requires phosphoinositide hydrolysis or Ca2+ mobilization. Through antibody microinjections and a genetic approach, we demonstrate tha t activation of the chloride conductance is mediated by Ga,, in a RhoA-inde pendent manner in both neuronal cells and fibroblasts, We further show that , in neuronal cells, this newly described Ga,, pathway may profoundly modul ate membrane excitability during RhoA-regulated neurite remodeling.