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      Role of K + Channels in Frequency Regulation of Spontaneous Action Potentials in Rat Pituitary GH 3 Cells

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          Abstract

          The frequency of spontaneous action potentials (SAP) is important in the regulation of hormone secretion. The decrease in K<sup>+</sup> conductance is known as a primary mechanism for increasing SAP frequency. To investigate the nature of K<sup>+</sup> channels that contribute to the frequency regulation of the SAP in rat clonal pituitary GH<sub>3</sub> cells, the effect of various K<sup>+</sup> channel blockers on the SAP and membrane currents were recorded using the patch-clamp technique. A classical inward rectifying K<sup>+</sup> channel blocker, Cs<sup>+</sup> (5 m M), caused an increase in firing frequency and depolarization in after-hyperpolarization (AHP) voltage. An ether-a-go-go (erg) type K<sup>+</sup> channel blocker, E-4031 (5 µ M), caused no significant effect on the SAP. Tetraethylammonium (TEA, 10 m M) decreased firing frequency and increased the duration of SAP. These effects were not changed by the presence of high concentration of Ca<sup>2+</sup> buffer (10 m M EGTA or BAPTA) in pipette solutions. In voltage-clamp experiments, Cs<sup>+</sup> and E-4031 did not affect outwardly rectifying K<sup>+</sup> currents, but significantly inhibited inwardly rectifying K<sup>+</sup> currents recorded in isotonic K<sup>+</sup> solution. However, the kinetics of Cs<sup>+</sup>-sensitive current and E-4031-sensitive current were distinctive: the time to peak was more immediate and the decay rate was slower in Cs<sup>+</sup>-sensitive current than in E-4031-sensitive current. These results imply that Cs<sup>+</sup> and E-4031 inhibit the distinct components of inwardly rectifying K<sup>+</sup> currents, and that the contribution of the Cs<sup>+</sup>-sensitive current can be immediate on repolarization and can last more effectively over pacemaking potential range than E-4031-sensitive current.

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          Most cited references 13

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          Calcium oscillations increase the efficiency and specificity of gene expression.

          Cytosolic calcium ([Ca2+]i) oscillations are a nearly universal mode of signalling in excitable and non-excitable cells. Although Ca2+ is known to mediate a diverse array of cell functions, it is not known whether oscillations contribute to the efficiency or specificity of signalling or are merely an inevitable consequence of the feedback control of [Ca2+]i. We have developed a Ca2+ clamp technique to investigate the roles of oscillation amplitude and frequency in regulating gene expression driven by the proinflammatory transcription factors NF-AT, Oct/OAP and NF-kappaB. Here we report that oscillations reduce the effective Ca2+ threshold for activating transcription factors, thereby increasing signal detection at low levels of stimulation. In addition, specificity is encoded by the oscillation frequency: rapid oscillations stimulate all three transcription factors, whereas infrequent oscillations activate only NF-kappaB. The genes encoding the cytokines interleukin (IL)-2 and IL-8 are also frequency-sensitive in a way that reflects their degree of dependence on NF-AT versus NF-kappaB. Our results provide direct evidence that [Ca2+]i oscillations increase both the efficacy and the information content of Ca2+ signals that lead to gene expression and cell differentiation.
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            Theoretical biology. A robust view of biochemical pathways.

             S Hartwell (1997)
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              The erg-like potassium current in rat lactotrophs.

              1. The ether-à-go-go-related gene (erg)-like K+ current in rat lactotrophs from primary culture was characterized and compared with that in clonal rat pituitary cells (GH3/B6). The class III antiarrhythmic E-4031 known to block specifically erg K+ channels was used to isolate the erg-like current as the E-4031-sensitive current. The experiments were performed in 150 mM K+ external solution using the patch-clamp technique. 2. The erg-like K+ current elicited with hyperpolarizing pulses negative to -100 mV consisted of a fast and a pronounced slowly deactivating current component. The contribution of the slow component to the total current amplitude was potential dependent and varied from cell to cell. At -100 mV it ranged from 50 to 85% and at -140 mV from 21 to 45%. 3. The potential-dependent channel availability curves determined with 2 s prepulses were fitted with the sum of two Boltzmann functions. The function related to the slowly deactivating component of the erg-like current was shifted by more than 40 mV to more negative membrane potentials compared with that of the fast component. 4. In contrast to that of native lactotrophs studied under identical conditions, the erg-like K+ current of GH3/B6 cells was characterized by a predominant fast deactivating current component, with similar kinetic and steady-state properties to the fast deactivating current component of native lactotrophs. 5. Thyrotrophin-releasing hormone reduced the erg-like current in native lactotrophs via an intracellular signal cascade which seemed to involve a pathway independent from protein kinase A and protein kinase C. 6. RT-PCR studies on cytoplasm from single lactotrophs revealed the presence of mRNA of the rat homologue of the human ether-à-go-go-related gene HERG (r-erg1) as well as mRNA of the two other cloned r-erg cDNAs (r-erg2 and r-erg3) in different combinations. In GH3/B6 cells, only the transcripts of r-erg1 and r-erg2 were found.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2003
                November 2003
                08 December 2003
                : 78
                : 5
                : 260-269
                Affiliations
                aDepartment of Physiology, Seoul National University, College of Medicine, Seoul; bBiomedical Research Center, Korea Institute of Science and Technology, Seoul, and cDepartment of Physiology, Gachon Medical School, Incheon, Korea
                Article
                74447 Neuroendocrinology 2003;78:260–269
                10.1159/000074447
                14657607
                © 2003 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: 30, Pages: 10
                Categories
                Reproductive Neuroendocrinology

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