Galpha(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 or G protein-coupled receptor (GPCR) agonists such as lysophosphatidic acid and thrombin. Membrane depolarization is due to the activation of a chloride conductance. While this response has received relatively little attention in the past, it is clear that the acute loss of membrane potential may have important physiological consequences. However, the dissection of the underlying G protein pathway and the establishment of cause-effect relationships have remained elusive to date. Here we report that, in neuronal 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 that activation of the chloride conductance is mediated by Galpha(13) in a RhoA-independent manner in both neuronal cells and fibroblasts. We further show that, in neuronal cells, this newly described Galpha(13) pathway may profoundly modulate membrane excitability during RhoA-regulated neurite remodeling.
Division of Cellular Biochemistry, The Netherlands Cancer Institute and Centre for Biomedical Genetics, Amsterdam 1066 CX, The Netherlands.
F R
FR
Postma
K
K
Jalink
T
T
Hengeveld
S
S
Offermanns
W H
WH
Moolenaar
D000200:Action Potentials; D000818:Animals; D002460:Cell Line; D018118:Chloride Channels / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000502:physiology*; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D009474:Neurons / Q000378:metabolism* / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D018118:Chloride Channels; D004268:DNA-Binding Proteins; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D020742:rhoA GTP-Binding Protein