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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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          Abstract

          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

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              Author and article information

              Journal
              NEN
              Neuroendocrinology
              10.1159/issn.0028-3835
              Neuroendocrinology
              S. Karger AG
              0028-3835
              1423-0194
              1999
              July 1999
              15 July 1999
              : 70
              : 1
              : 1-9
              Affiliations
              Departments of aAnatomy and Neurosciences and bPhysiology and Biophysics, University of Texas Medical Branch at Galveston, Galveston, Tex., USA
              Article
              54454 Neuroendocrinology 1999;70:1–9
              10.1159/000054454
              10420088
              © 1999 S. Karger AG, Basel

              Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

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

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