Thyrotropin releasing hormone inhibits tau phosphorylation by dual signaling pathways in hippocampal neurons.
Depletion of thyrotropin releasing hormone (TRH) gene expression resulted in augmented tau and glycosynthetase kinase-3beta (GSK-3beta), in contrast, TRH administration resulted in decreases of 75% in GSK-3beta and 90% in Tau phosphorylation in cultured rat hippocampal neurons. To further study TRH regulation of tau phosphorylation, immunoblotting was used to explore G-protein coupled TRH receptor activation of the phosphokinase C (PKC) and phosphokinase A (PKA) signaling pathways. TRH was found to rapidly activate PKA (2.5 fold in 10 min) while it suppressed PKC (levels decreased by 85% vs. control) in hippocampal neurons. This process was also discovered to be a cell type-specific response, as TRH activated PKC in only hypothalamic neurons. Further investigation revealed that the Src inhibitor Protein Phosphatase 2 (PP2, 50 uM) could block TRH inhibition of PKC, GSK-3beta, and tau phosphorylation with no effects on PKA. In addition, the PKC inhibitor GF109203 Bis (10 uM) was also able to suppress TRH inhibition of GSK-3beta, leading to increased GSK-3 beta activity. Independent of these effects, inhibition of PKA by H89 (10 uM) significantly blocked TRH inhibition of GSK-3 beta. These data suggests that both PKA and PKC are independently crucial to TRH's effects on GSK-3 beta, and support the roles of two distinct pathways involving suppression of PKC via the Src kinase and activation of PKA in mediating TRH effects on GSK-3 beta and tau. These dual signaling pathways between TRH and tau may provide mechanisms for the precise regulation of tau phosphorylation and dephosphorylation in neurons.
Luo
Luguang
L
Department of Research, Center for Stem Cell Biology, Department of Research, Roger Williams Medical Center, Chalkstone, RI, USA. Lluo@RWMC.org
Stopa
Edward G
EG
D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D015151:Immunoblotting; D009474:Neurons / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013973:Thyrotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins; D013973:Thyrotropin-Releasing Hormone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D038362:Glycogen Synthase Kinase 3