Rac and Rho mediate opposing hormonal regulation of the ether-a-go-go-related potassium channel.
BACKGROUND
Previous studies of ion channel regulation by G proteins have focused on the larger, heterotrimeric GTPases, which are activated by heptahelical membrane receptors. In contrast, studies of the Rho family of smaller, monomeric, Ras-related GTPases, which are activated by cytoplasmic guanine nucleotide exchange factors, have focused on their role in cytoskeletal regulation.


RESULTS
Here we demonstrate novel functions for the Rho family GTPases Rac and Rho in the opposing hormonal regulation of voltage-activated, ether-a-go-go-related potassium channels (ERG) in a rat pituitary cell line, GH(4)C(1). The hypothalamic neuropeptide, thyrotropin-releasing hormone (TRH) inhibits ERG channel activity through a PKC-independent process that is blocked by RhoA(19N) and the Clostridium botulinum C3 toxin, which inhibit Rho signaling. The constitutively active, GTPase-deficient mutant of RhoA(63L) rapidly inhibits the channels when the protein is dialysed directly into the cell through the patch pipette, and inhibition persists when the protein is overexpressed. In contrast, GTPase-deficient Rac1(61L) stimulates ERG channel activity. The thyroid hormone triiodothyronine (T3), which antagonizes TRH action in the pituitary, also stimulates ERG channel activity through a rapid process that is blocked by Rac1(17N) and wortmannin but not by RhoA(19N).


CONCLUSIONS
Rho stimulation by G(13)-coupled receptors and Rac stimulation by nuclear hormones through PI3-kinase may be general mechanisms for regulating ion channel activity in many cell types. Disruption of these novel signaling cascades is predicted to contribute to several specific human neurological diseases, including epilepsy and deafness.
Storey
Nina M
NM
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
O'Bryan
John P
JP
Armstrong
David L
DL
D000200:Action Potentials; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D000072237:ERG1 Potassium Channel; D004553:Electric Conductivity; D051638:Ether-A-Go-Go Potassium Channels; D007700:Kinetics; D009154:Mutation; D018408:Patch-Clamp Techniques; D010902:Pituitary Gland / Q000502:physiology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D015398:Signal Transduction; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology; D014284:Triiodothyronine / Q000494:pharmacology; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000502:physiology*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein