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      Intracellular pH as a Determinant of Vascular Smooth Muscle Function

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          Abstract

          Intracellular pH (pH<sub>i</sub>) is a physiological parameter that is intimately linked to contractility, growth and proliferation of vascular smooth muscle (VSM). Regarding contractility, no general unifying concept of pH<sub>i</sub> regulation but a rather complex relation between pH<sub>i</sub> signals and vascular tone has been revealed so far. The modulation of vasotone by pH<sub>i</sub> depends on the type of blood vessel as well as on the pattern of regulatory input signals. In addition, changes in pH<sub>i</sub> have been recognized as an important cellular signal to determine the fate of cells in terms of proliferation or apoptosis. Cellular sensors for pH<sub>i</sub> include a variety of ion transport systems which control intracellular Ca<sup>2+</sup> gradients and are likely to serve as a link between pH<sub>i</sub> and cell functions. Here we provide an overview on the potential targets and mechanisms that transduce pH<sub>i</sub> signals in VSM. The role of pH<sub>i</sub>-sensing signaling complexes and localized pH<sub>i</sub> signaling as the basis of diversity of pH<sub>i</sub> regulation of VSM function is discussed.

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          Most cited references44

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          Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes.

          In this study we investigate the mechanism of intracellular pH change and its role in malignant transformation using the E7 oncogene of human papillomavirus type 16 (HPV16). Infecting NIH3T3 cells with recombinant retroviruses expressing the HPV16 E7 or a transformation deficient mutant we show that alkalinization is transformation specific. In NIH3T3 cells in which transformation can be turned on and followed by induction of the HPV16 E7 oncogene expression, we demonstrate that cytoplasmic alkalinization is an early event and was driven by stimulation of Na+/H+ exchanger activity via an increase in the affinity of the intracellular NHE-1 proton regulatory site. Annulment of the E7-induced cytoplasmic alkalinization by specific inhibition of the NHE-1, acidification of culture medium, or clamping the pHi to nontransformed levels prevented the development of later transformed phenotypes such as increased growth rate, serum-independent growth, anchorage-independent growth, and glycolytic metabolism. These findings were verified in human keratinocytes (HPKIA), the natural host of HPV. Results from both NIH3T3 and HPKIA cells show that alkalinization acts on pathways that are independent of the E2F-mediated transcriptional activation of cell cycle regulator genes. Moreover, we show that the transformation-dependent increase in proliferation is independent of the concomitant stimulation of glycolysis. Finally, treatment of nude mice with the specific inhibitor of NHE-1, DMA, delayed the development of HPV16-keratinocyte tumors. Our data confirm that activation of the NHE-1 and resulting cellular alkalinization is a key mechanism in oncogenic transformation and is necessary for the development and maintenance of the transformed phenotype.
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            An intracellular proton sensor commands lipid- and mechano-gating of the K(+) channel TREK-1.

            The 2P domain K(+) channel TREK-1 is widely expres sed in the nervous system. It is opened by a variety of physical and chemical stimuli including membrane stretch, intracellular acidosis and polyunsaturated fatty acids. This activation can be reversed by PKA-mediated phosphorylation. The C-terminal domain of TREK-1 is critical for its polymodal function. We demonstrate that the conversion of a specific glutamate residue (E306) to an alanine in this region locks TREK-1 in the open configuration and abolishes the cAMP/PKA down-modulation. The E306A substitution mimics intracellular acidosis and rescues both lipid- and mechano-sensitivity of a loss-of-function truncated TREK-1 mutant. We conclude that protonation of E306 tunes the TREK-1 mechanical setpoint and thus sets lipid sensitivity.
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              Dephosphorylation of the calcium pump coupled to counterion occlusion.

              P-type ATPases extract energy by hydrolysis of adenosine triphosphate (ATP) in two steps, formation and breakdown of a covalent phosphoenzyme intermediate. This process drives active transport and countertransport of the cation pumps. We have determined the crystal structure of rabbit sarcoplasmic reticulum Ca2+ adenosine triphosphatase in complex with aluminum fluoride, which mimics the transition state of hydrolysis of the counterion-bound (protonated) phosphoenzyme. On the basis of structural analysis and biochemical data, we find this form to represent an occluded state of the proton counterions. Hydrolysis is catalyzed by the conserved Thr-Gly-Glu-Ser motif, and it exploits an associative nucleophilic reaction mechanism of the same type as phosphoryl transfer from ATP. On this basis, we propose a general mechanism of occluded transition states of Ca2+ transport and H+ countertransport coupled to phosphorylation and dephosphorylation, respectively.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2006
                May 2006
                17 May 2006
                : 43
                : 3
                : 238-250
                Affiliations
                aDepartment of Hygiene and Preventive Medicine, Yamagata University School of Medicine, Yamagata, Japan; bDepartment of Pharmaceutical Sciences, Pharmacology and Toxicology, University of Graz, Graz, Austria
                Article
                91235 J Vasc Res 2006;43:238–250
                10.1159/000091235
                16449818
                72754422-f5bb-481f-923a-cb4fced5c3d8
                © 2006 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.

                History
                : 24 May 2005
                : 20 November 2005
                Page count
                Figures: 2, References: 100, Pages: 13
                Categories
                Review

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                Smooth muscle proliferation,Cellular pH sensors,Vasoconstriction,Intracellular pH,Vascular smooth muscle

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