TRH regulates Kv1.5 gene expression through a Galphaq-mediated PLC-independent pathway.
Thyrotropin-releasing hormone (TRH) decreases transcription of the Kv1.5 K(+) channel gene in GH(3) pituitary cells. Here, we examine whether TRH utilizes Gq activated phospholipase C, Gs or Gi to produce this response. We report that expression of constitutively active Galphaq mimicked and occluded the TRH effect. In contrast, expression of activated Galpha(S) or Galpha(i2) had no effect on Kv1. 5 mRNA expression. Furthermore, pertussis and cholera toxins failed to block the TRH-induced decrease in channel mRNA. Surprisingly, despite the role of Gq, the phospholipase C inhibitor U73122 did not alter down-regulation of channel mRNA by TRH, although it abolished the TRH-induced increase in intracellular [Ca(2+)] and up-regulation of c-fos mRNA. Furthermore, depletion of an intracellular Ca(2+) pool or inhibition of protein kinase C did not block the TRH-induced decrease in Kv1.5 mRNA. These results indicate that TRH-induced down-regulation of Kv1.5 gene expression is mediated by Galphaq proteins, but does not require PLC activation.
Department of Pharmacology, University of Pittsburgh, E1351 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
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Zhang
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Gealy
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Lu
L E
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Heasley
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Takimoto
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ES
Levitan
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005786:Gene Expression Regulation / Q000187:drug effects; D016762:Genes, fos / Q000187:drug effects; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D051666:Kv1.5 Potassium Channel; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics*; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011760:Pyrrolidinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism
D004791:Enzyme Inhibitors; D004963:Estrenes; C496983:Kcna5 protein, rat; D051666:Kv1.5 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011760:Pyrrolidinones; D012333:RNA, Messenger; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; D013973:Thyrotropin-Releasing Hormone; D011493:Protein Kinase C; D010738:Type C Phospholipases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins