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      Expression of the L-Type Ca 2+ Channel in AtT-20 Cells Is Regulated by Cyclic AMP

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          Activation of adenylyl cyclase by corticotropin-releasing hormone (CRH) stimulates secretion of adrenocorticotropin (ACTH) in rat anterior pituitary corticotropes and in the murine AtT-20 cell line. The stimulation of secretion is mediated by cAMP and is largely dependent on Ca<sup>2+</sup> influx through voltage-gated L-type Ca<sup>2+</sup> channels. To investigate whether CRH and cAMP also increase expression of the L-type Ca<sup>2+</sup> channel in AtT-20 cells, an RNase protection assay was used to measure the α<sub>1C</sub> mRNA that encodes the pore-forming subunit of the L-type Ca<sup>2+</sup> channel. The α<sub>1C</sub> mRNA level was measured by autoradiographic densitometry and normalized to the β-actin mRNA level in the same sample. The α<sub>1C</sub> mRNA was not changed by 24-hour treatment with CRH (10–500 n M). A 24-hour treatment with 1 m M 8Br-cAMP significantly increased the α<sub>1C</sub> mRNA by 40% over its control. The stimulatory effect was blocked by 2 µ M actinomycin D and was, therefore, dependent on gene transcription. The measured half-life of the α<sub>1C</sub> mRNA, after inhibition of transcription, was 4.7 ± 0.3 h in control and 5.2 ± 0.6 h in the presence of 8Br-cAMP. Thus the 8Br-cAMP- induced increase in α<sub>1C</sub> mRNA could be due to an increase in α<sub>1C</sub> gene transcription or to a transcriptionally regulated increase in a protein that helps to stabilize α<sub>1C</sub> mRNA. Finally, to determine if the increased mRNA was followed by an increase in production of L-type Ca<sup>2+</sup> channels, the binding of [<sup>3</sup>H]PN200-110 to Ca<sup>2+</sup> channel proteins was assayed in AtT-20 membrane fragments. 8Br-cAMP increased [<sup>3</sup>H]PN200-110 binding sites by 32% (B<sub>max</sub> 36.0 ± 1.2 fmol/mg protein in control vs. 47.4 ± 3.2 fmol/mg protein in 8Br-cAMP-treated cells) but did not change the K<sub>d</sub>. These studies show that both α<sub>1C</sub> mRNA and L-type Ca<sup>2+</sup> channel protein are increased in AtT-20 cells by cAMP.

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          Regulation of cAMP-inducible genes by CREB.

          A large number of neuropeptides and neurotransmitters stimulate neuronal cells through the second messenger cAMP. These synaptic signals often cause profound changes in neuronal function by altering basic patterns of gene expression. Cyclic AMP, in turn, regulates a number of these genes through a conserved cAMP response element (CRE). Recently, a nuclear CRE-binding protein, CREB, has been shown to bind to the CRE and stimulate the transcription of cAMP-responsive genes. This article reviews recent progress towards understanding the mechanism by which cAMP modulates the activity of CREB to stimulate gene transcription.
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            Corticotropin-releasing factor stimulates adenylate cyclase activity in the anterior pituitary gland


              Author and article information

              S. Karger AG
              July 1999
              15 July 1999
              : 70
              : 1
              : 1-9
              Departments of aAnatomy and Neurosciences and bPhysiology and Biophysics, University of Texas Medical Branch at Galveston, Galveston, Tex., USA
              54454 Neuroendocrinology 1999;70:1–9
              © 1999 S. Karger AG, Basel

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              Page count
              Figures: 6, References: 41, Pages: 9
              Regulation of Pituitary Ca 2+ Channels


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