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      Orexin-B Augments Voltage-Gated L-Type Ca 2+ Current via Protein Kinase C-Mediated Signalling Pathway in Ovine Somatotropes

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          Abstract

          Orexins, orexigenic neuropeptides, are secreted from lateral hypothalamus and orexin receptors are expressed in the pituitary. Since growth hormone (GH) secreted from pituitary is integrally linked to energy homeostasis and metabolism, we studied the effect of orexin-B on voltage-gated Ca<sup>2+</sup> currents and the related signalling mechanisms in primary cultured ovine somatotropes using whole-cell patch-clamp techniques. With a bath solution containing TEA-Cl (40 m M) and Tetrodotoxin (TTX) (1 µ M), three subtypes of Ca<sup>2+</sup> currents, namely the long-lasting (L), transient (T), and N currents, were isolated using different holding potentials (–80 and –30 mV) in combination with specific Ca<sup>2+</sup> channel blockers (nifedipine and ω-conotoxin). About 75% of the total current amplitude was contributed by the L current, whereas the N and T currents accounted for the rest. Orexin-B (1–100 n M) dose-dependently and reversibly increased only the L current up to approximately 125% of the control value within 4–5 min. Neither a specific protein kinase A (PKA) blocker (H89, 1 µ M) nor an inhibitory peptide (PKI, 10 µ M) had any effect on the increase in L current by orexin-B. The orexin-B-induced increase in the L current was abolished by concurrent treatment with calphostin C (Cal-C, 100 n M), protein kinase C (PKC) inhibitory peptide (PKC<sub>19–36</sub>, 1 µ M), or by pretreatment with phorbol-12,13-dibutyrate (PDBu) (0.5 µ M) for 16 h (a downregulator of PKC). Orexin-B also increased in vitro GH secretion in a dose-dependent manner. We conclude that orexin-B increases the L-type Ca<sup>2+</sup> current and GH secretion through orexin receptors and PKC-mediated signalling pathways in ovine somatotropes.

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          Most cited references 27

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          Orexins and Orexin Receptors: A Family of Hypothalamic Neuropeptides and G Protein-Coupled Receptors that Regulate Feeding Behavior

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            Orexin A activates locus coeruleus cell firing and increases arousal in the rat

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              Expression of P2X2 and P2X3 receptor subunits in rat carotid body afferent neurones: role in chemosensory signalling.

              1. Hypoxic chemotransmission in the rat carotid body (CB) is mediated in part by ATP acting on suramin-sensitive P2X purinoceptors. Here, we use RT-PCR, cloning and sequencing techniques to show P2X2 and P2X3 receptor expression in petrosal neurones, some of which develop functional chemosensory units with CB receptor clusters in co-culture. 2. Single-cell RT-PCR revealed that hypoxia-responsive neurones, identified electrophysiologically in co-culture, expressed both P2X2 and P2X3 mRNA. 3. Isohydric hypercapnia (10 % CO(2); pH 7.4) caused excitation of chemosensory units in co-culture. This excitation depended on chemical transmission, with ATP acting as a co-transmitter, since it was inhibited by reduction of the extracellular Ca(2+):Mg(2+) ratio and by the purinoceptor blocker suramin (50-100 microM). 4. Hypoxia and isohydric hypercapnia could separately excite the same chemosensory unit, and together the two stimuli interacted synergistically. 5. Using confocal immunofluorescence, co-localization of P2X2 and P2X3 protein was demonstrated in many petrosal somas and CB afferent terminals in situ. Taken together, these data indicate that ATP and P2X2-P2X3 purinoceptors play important roles in the peripheral control of respiration by carotid body chemoreceptors.
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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
                March 2003
                03 April 2003
                : 77
                : 3
                : 141-152
                Affiliations
                aPrince Henry’s Institute of Medical Research, bDepartment of Physiology, Monash University, Clayton, Vic., Australia; cLaboratory of Animal Molecular Physiology, Faculty of Agriculture, Shinshu University, Naganoken, and dDepartment of Physiology, University of Occupational and Environmental Health, Kitakyushu, Japan
                Article
                69507 Neuroendocrinology 2003;77:141–152
                10.1159/000069507
                12673048
                © 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: 7, References: 63, Pages: 12
                Categories
                Cellular Neuroendocrinology

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