text: GnRH pulse frequency-dependent stimulation of FSHβ transcription is mediated via activation of PKA and CREB.
  Expression of pituitary FSH and LH, under the control of pulsatile GnRH, is essential for fertility. cAMP response element-binding protein (CREB) has been implicated in the regulation of FSHβ gene expression, but the molecular mechanisms by which pulsatile GnRH regulates CREB activation remain poorly understood. We hypothesized that CREB is activated by a distinct signaling pathway in response to pulsatile GnRH in a frequency-dependent manner to dictate the FSHβ transcriptional response. GnRH stimulation of CREB phosphorylation (pCREB) in the gonadotrope-derived LβT2 cell line was attenuated by a protein kinase A (PKA) inhibitor, H89. A dominant negative PKA (DNPKA) reduced GnRH-stimulated pCREB and markedly decreased GnRH stimulation of FSHβ mRNA and FSHβLUC activity, but had little effect on LHβLUC activity, indicating relative specificity of this pathway. In perifusion studies, FSHβ mRNA levels and FSHβLUC activities were increased by pulsatile GnRH, with significantly greater increases at low compared with high pulse frequencies. DNPKA markedly reduced these GnRH-stimulated FSHβ responses at both low and high pulse frequencies. Correlating with FSHβ activation, both PKA activity and levels of pCREB were increased to a greater extent by low compared with high GnRH pulse frequencies, and the induction of pCREB was also attenuated by overexpression of DNPKA at both low and high pulse frequencies. Taken together, these data indicate that a PKA-mediated signaling pathway mediates GnRH activation of CREB at low-pulse frequencies, playing a significant role in the decoding of the hypothalamic GnRH signal to result in frequency-dependent FSHβ activation.
entities.id: T10 T11 T12 T13 T14 T15 T16 T17 T18 T19 T1 T20 T21 T22 T23 T24 T25 T26 T27 T28 T29 T2 T30 T31 T32 T33 T34 T35 T36 T37 T38 T39 T3 T40 T41 T42 T43 T44 T45 T46 T47 T48 T49 T4 T50 T51 T52 T53 T54 T55 T56 T57 T58 T59 T5 T6 T7 T8 T9
entities.type: CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-N GENE-N GENE-Y GENE-Y CHEMICAL GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-Y GENE-Y GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-Y GENE-N CHEMICAL GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N GENE-N CHEMICAL GENE-Y GENE-Y GENE-Y GENE-Y GENE-Y GENE-N GENE-N GENE-N GENE-Y GENE-N CHEMICAL CHEMICAL CHEMICAL CHEMICAL CHEMICAL
entities.text: GnRH GnRH GnRH GnRH GnRH cAMP response element-binding protein DNPKA GnRH FSHβ FSHβ cAMP PKA pCREB GnRH pCREB DNPKA CREB PKA GnRH CREB GnRH GnRH FSHβ FSHβ FSH GnRH CREB LH CREB GnRH FSHβ GnRH GnRH CREB pCREB protein kinase A PKA dominant negative PKA DNPKA GnRH GnRH pCREB GnRH GnRH FSHβ FSHβ LHβ FSHβ FSHβ GnRH GnRH CREB FSHβ PKA GnRH GnRH GnRH GnRH H89