MINIREVIEW Osmosensing and signaling in the regulation of mammalian cell function Freimut Schliess, Roland Reinehr and Dieter Ha ¨ ussinger Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Du ¨ sseldorf, Germany Introduction Sudden exposure of cells to hypo- or hyperosmotic solutions induces a rapid osmotic swelling or shrink- age, respectively. Extensive swelling or shrinkage is counteracted by induction of a regulatory volume decrease (RVD) or increase, respectively [1–3]. Most hypoosmotically swollen cells perform RVD by a release of inorganic ions, including K + ,Na + ,Cl – , and HCO 3 – and organic osmolytes (e.g. taurine, betaine). Hyperosmotic regulatory volume increase (RVI) at a short-term time scale is performed by activation of electrolyte uptake (e.g. via Na + ⁄ K + ⁄ 2Cl – cotransport and Na + ⁄ H + exchange). Long-term adaption to hyperosmolarity includes an isoosmotic exchange of inorganic ions against compatible organic osmolytes, which preserve protein function even at high concen- trations [4]. Transport systems involved in RVD or RVI can be activated also by hormones, substrates, second messen- gers and oxidative stress under isoosmotic conditions. In these cases, moderate and well-tolerated cell volume changes are created. For example, insulin produces a phosphoinositide 3-kinase (PI 3-kinase)-dependent hepatocyte swelling by inducing a net accumulation of ions inside the cell, which results from a concerted activation of Na + ⁄ H + exchange, Na + ⁄ K + ⁄ 2Cl – sym- port and the Na + ⁄ K + -ATPase [5]. In the early 1990s, it was recognized, that cell vol- ume changes trigger signals involved in the regulation of metabolism, gene expression and the susceptibility to different kinds of stress [6]. For example, the inhibi- tion of autophagic proteolysis by insulin, glutamine and ethanol in the perfused liver critically depends on the degree of hepatocyte swelling induced by these stimuli and can be mimicked by hypoosmotic swelling Keywords apoptosis; bile acids; CD95; cell volume; epidermal growth factor; insulin; integrins; osmolytes; oxidative stress; proliferation Correspondence F. Schliess, Heinrich-Heine-Universita ¨ t, Universita ¨ tsklinikum, Klinik fu ¨ r Gastroenterologie und Infektiologie, Moorenstrasse 5, D-40225 Du ¨ sseldorf, Germany Fax: +49 211 81 17517 Tel: +49 211 81 18941 E-mail: schliess@med.uni-duesseldorf.de (Received 2 July 2007, accepted 29 August 2007) doi:10.1111/j.1742-4658.2007.06100.x Volume changes of mammalian cells as induced by either anisoosmolarity or under isoosmotic conditions by hormones, substrates and oxidative stress critically contribute to the regulation of metabolism, gene expression and the susceptibility to stress. Osmosensing (i.e. the registration of cell volume) triggers signal transduction pathways towards effector sites (osmo- signaling), which link alterations of cell volume to a functional outcome. This minireview summarizes recent progress in the understanding of how osmosensing and osmosignaling integrate into the overall context of growth factor signaling and the execution of apoptotic programs. Abbreviations EGF, epidermal growth factor; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphoinositide 3-kinase; RGD, arginine-glycine- aspartic acid; ROS, reactive oxygen species; RVD, regulatory volume decrease; RVI, regulatory volume increase. FEBS Journal 274 (2007) 5799–5803 ª 2007 The Authors Journal compilation ª 2007 FEBS 5799 [7]. On the other hand, hyperosmotic shrinkage pre- vents insulin-induced hepatocyte Endocrine Regulation of Kidney Function Endocrine Regulation of Kidney Function Bởi: OpenStaxCollege Several hormones have specific, important roles in regulating kidney function They act to stimulate or inhibit blood flow Some of these are endocrine, acting from a distance, whereas others are paracrine, acting locally Renin–Angiotensin–Aldosterone Renin is an enzyme that is produced by the granular cells of the afferent arteriole at the JGA It enzymatically converts angiotensinogen (made by the liver, freely circulating) into angiotensin I Its release is stimulated by prostaglandins and NO from the JGA in response to decreased extracellular fluid volume ACE is not a hormone but it is functionally important in regulating systemic blood pressure and kidney function It is produced in the lungs but binds to the surfaces of endothelial cells in the afferent arterioles and glomerulus It enzymatically converts inactive angiotensin I into active angiotensin II ACE is important in raising blood pressure People with high blood pressure are sometimes prescribed ACE inhibitors to lower their blood pressure Angiotensin II is a potent vasoconstrictor that plays an immediate role in the regulation of blood pressure It acts systemically to cause vasoconstriction as well as constriction of both the afferent and efferent arterioles of the glomerulus In instances of blood loss or dehydration, it reduces both GFR and renal blood flow, thereby limiting fluid loss and preserving blood volume Its release is usually stimulated by decreases in blood pressure, and so the preservation of adequate blood pressure is its primary role Aldosterone, often called the “salt-retaining hormone,” is released from the adrenal cortex in response to angiotensin II or directly in response to increased plasma K+ It promotes Na+ reabsorption by the nephron, promoting the retention of water It is also important in regulating K+, promoting its excretion (This dual effect on two minerals and its origin in the adrenal cortex explains its designation as a mineralocorticoid.) As a 1/5 Endocrine Regulation of Kidney Function result, renin has an immediate effect on blood pressure due to angiotensin II–stimulated vasoconstriction and a prolonged effect through Na+ recovery due to aldosterone At the same time that aldosterone causes increased recovery of Na+, it also causes greater loss of K+ Progesterone is a steroid that is structurally similar to aldosterone It binds to the aldosterone receptor and weakly stimulates Na+ reabsorption and increased water recovery This process is unimportant in men due to low levels of circulating progesterone It may cause increased retention of water during some periods of the menstrual cycle in women when progesterone levels increase Antidiuretic Hormone (ADH) Diuretics are drugs that can increase water loss by interfering with the recapture of solutes and water from the forming urine They are often prescribed to lower blood pressure Coffee, tea, and alcoholic beverages are familiar diuretics ADH, a 9-amino acid peptide released by the posterior pituitary, works to the exact opposite It promotes the recovery of water, decreases urine volume, and maintains plasma osmolarity and blood pressure It does so by stimulating the movement of aquaporin proteins into the apical cell membrane of principal cells of the collecting ducts to form water channels, allowing the transcellular movement of water from the lumen of the collecting duct into the interstitial space in the medulla of the kidney by osmosis From there, it enters the vasa recta capillaries to return to the circulation Water is attracted by the high osmotic environment of the deep kidney medulla Endothelin Endothelins, 21-amino acid peptides, are extremely powerful vasoconstrictors They are produced by endothelial cells of the renal blood vessels, mesangial cells, and cells of the DCT Hormones stimulating endothelin release include angiotensin II, bradykinin, and epinephrine They not typically influence blood pressure in healthy people On the other hand, in people with diabetic kidney disease, endothelin is chronically elevated, resulting in sodium retention They also diminish GFR by damaging the podocytes and by potently vasoconstricting both the afferent and efferent arterioles Natriuretic Hormones Natriuretic hormones are peptides that stimulate the kidneys to excrete sodium—an effect opposite that of aldosterone Natriuretic hormones act by inhibiting aldosterone release and therefore inhibiting Na+ recovery in the collecting ducts If Na+ remains in the forming urine, its osmotic force will cause a concurrent loss of water Natriuretic hormones also inhibit ADH release, which of course will result in less water recovery Therefore, natriuretic peptides inhibit both Na+ and water recovery One example from 2/5 Endocrine Regulation of Kidney Function this family of hormones is atrial natriuretic hormone (ANH), a 28-amino acid peptide produced by heart atria in response to ...Roles of the SH2 and SH3 domains in the regulation of neuronal Src kinase functions Bradley R. Groveman 1 , Sheng Xue 2 , Vedrana Marin 1 , Jindong Xu 2 , Mohammad K. Ali 1 , Ewa A. Bienkiewicz 1 and Xian-Min Yu 1,2 1 Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, USA 2 Faculty of Dentistry, University of Toronto, Ontario, Canada Introduction Src family kinases (SFKs) are critically involved in the regulation of many biological functions mediated through growth factors, G-protein-coupled receptors or ligand-gated ion channels. As such, SFKs have become important targets for therapeutic treatments [1,2]. Based on crystallographic studies of inactive and active Src, the SH2 and SH3 domains are believed to form a ‘regulatory apparatus’. Binding of the phos- phorylated C-terminus to the SH2 domain and ⁄ or binding of the SH2-kinase linker to the SH3 domain inactivates SFKs [3–6]. It has been shown that mutating Tyr527 to phenylalanine (Y527F) in the Keywords NMDA receptor regulation; phosphorylation; Src; the SH2 domain; the SH3 domain Correspondence X M. Yu, 1115 West Call Street, Tallahassee, FL 32306-4300, USA Fax: +1 850 644 5781 Tel: +1 850 645 2718 E-mail: xianmin.yu@med.fsu.edu (Received 10 September 2010, revised 3 November 2010, accepted 6 December 2010) doi:10.1111/j.1742-4658.2010.07985.x Previous studies demonstrated that intra-domain interactions between Src family kinases (SFKs), stabilized by binding of the phosphorylated C-terminus to the SH2 domain and ⁄ or binding of the SH2 kinase linker to the SH3 domain, lock the molecules in a closed conformation, disrupt the kinase active site, and inactivate SFKs. Here we report that the up-regula- tion of N-methyl- D-aspartate receptors (NMDARs) induced by expression of constitutively active neuronal Src (n-Src), in which the C-terminus tyro- sine is mutated to phenylalanine (n-Src ⁄ Y535F), is significantly reduced by dysfunctions of the SH2 and ⁄ or SH3 domains of the protein. Furthermore, we found that dysfunctions of SH2 and ⁄ or SH3 domains reduce auto- phosphorylation of the kinase activation loop, depress kinase activity, and decrease NMDAR phosphorylation. The SH2 domain plays a greater regu- latory role than the SH3 domain. Our data also show that n-Src binds directly to the C-terminus of the NMDAR NR2A subunit in vitro, with a K D of 108.2 ± 13.3 nM. This binding is not Src kinase activity-dependent, and dysfunctions of the SH2 and ⁄ or SH3 domains do not significantly affect the binding. These data indicate that the SH2 and SH3 domains may function to promote the catalytic activity of active n-Src, which is impor- tant in the regulation of NMDAR functions. Structured digital abstract l MINT-8074560: NR2A (uniprotkb:Q00959) binds (MI:0407)ton-Src (uniprotkb:P05480)by surface plasmon resonance ( MI:0107) l MINT-8074641, MINT-8074668, MINT-8074679, MINT-8074693, MINT-8074813: n-Src (uniprotkb: P05480) and n-Src (uniprotkb:P05480) phosphorylate (MI:0217)byprotein kinase assay ( MI:0424) l MINT-8074576, MINT-8074726, MINT-8074741, MINT-8074777: n-Src (uniprotkb:P05480) phosphorylates ( MI:0217) NR2A (uniprotkb:Q00959)byprotein kinase assay (MI:0424) Abbreviations c-Src, cellular Src; NMDAR, MINIREVIEW Protein transport in organelles: The composition, function and regulation of the Tic complex in chloroplast protein import J. Philipp Benz 1,2 ,Ju ¨ rgen Soll 1,2 and Bettina Bo ¨ lter 1,2 1 Plant Biochemistry, Ludwig-Maximilians-Universita ¨ tMu ¨ nchen, Munich, Germany 2 Munich Center for Integrated Protein Science CiPS M , Ludwig-Maximilians-Universita ¨ tMu ¨ nchen, Munich, Germany Introduction To fulfil their functions correctly, plastids permanently communicate with the surrounding cell. This requires a substantial traffic of substances such as nutrients, metabolites and proteins into and out of the organelle, which have to be funnelled across the two envelope membranes surrounding all plastid types. Among these transport processes, the translocation of proteins is of particular significance. Due to the loss of more than 90% of their genetic information to the host nucleus during evolution, plastids have become almost com- pletely dependent on the surrounding cell. Of the approximately 3000 proteins present in chloroplasts, typically only 50–250 (dependent on the species) are still encoded for on the plastome [1]. The majority of Keywords chloroplast; import motor; preprotein channel; redox regulation; Tic complex; translocon Correspondence J. Soll, Plant Biochemistry, Ludwig- Maximilians-Universita ¨ tMu ¨ nchen, Großhaderner Strasse 2-4, D-82152 Munich, Germany Fax: +49 89 2180 74752 Tel: +49 89 2180 74750 E-mail: soll@lmu.de Website: http://www.chloroplasts.de (Received 31 July 2008, accepted 11 December 2008) doi:10.1111/j.1742-4658.2009.06874.x It is widely accepted that chloroplasts derived from an endosymbiotic event in which an early eukaryotic cell engulfed an ancient cyanobacterial pro- karyote. During subsequent evolution, this new organelle lost its autonomy by transferring most of its genetic information to the host cell nucleus and therefore became dependent on protein import from the cytoplasm. The so-called ‘general import pathway’ makes use of two multisubunit protein translocases located in the two envelope membranes: the Toc and Tic com- plexes (translocon at the outer/inner envelope membrane of chloroplasts). The main function of both complexes, which are thought to work in para- llel, is to provide a protein-selective channel through the envelope mem- brane and to exert the necessary driving force for the translocation. To achieve high efficiency of protein import, additional regulatory subunits have been developed that sense, and quickly react to, signals giving infor- mation about the status and demand of the organelle. These include calcium-mediated signals, most likely through a potential plastidic calmod- ulin, as well as redox sensing (e.g. via the stromal NADP + /NADPH pool). In this minireview, we briefly summarize the present knowledge of how the Tic complex adapted to the tasks outlined above, focusing more on the recent advances in the field, which have brought substantial progress concerning the motor function as well as the regulatory potential of this protein translocation system. Abbreviations CaM, calmodulin; ClpC, caseinolytic protease C; Cpn, chaperonin; FNR, ferredoxin-NADP + -oxidoreductase; Hip, Hsp70-interacting protein; Hop, Hsp70/Hsp90-organizing protein; Hsp, heat shock protein; IEM, inner envelope membrane; OEM, outer envelope membrane; SDR, short-chain dehydrogenase; SPP, stromal processing peptidase; Tic, translocon at the inner envelope membrane of 531 GFR = glomerular filtration rate. Available online http://ccforum.com/content/9/5/531 We read with interest the article by Villa and coworkers [1] advocating the use of cystatin C as a measure of glomerular filtration rate (GFR) in critically ill patients. However, we should like to draw attention to several flaws in this study. First, Villa and coworkers compared cystatin C with creatinine as a measure of GFR, using body surface corrected creatinine clearance as, what they call, a ‘gold standard’. However, in the Discussion section of that report inulin and iothalamate clearances are mentioned as gold standards, but they were not used by these investigators. The use of body surface area corrected creatinine clearance is questionable in both obese and excessively lean individuals because the correlation between surface area and lean body mass may be lost. Both types of patients are frequently encountered in intensive care. Second, Villa and coworkers employ a cutoff of 80 ml/min to identify renal dysfunction, whereas a value of 50 ml/min is generally accepted [2]. This could have a major influence on the presented results. Third, patients with thyroid disorders or on corticosteroid therapy were excluded. Almost all patients with critical illness have low tri-iodothyronine values because of changes in thyroid hormone metabolism (‘nonthyroidal illness’), thus making recognition of thyroid disorders problematic. Finally, we showed [3] that, in patients with thyroid dysfunction, cystatin C is not a suitable measure of GFR. In hypothyroidism creatinine levels are elevated but cystatin C levels are low, whereas in hyperthyroidism creatinine levels are low and cystatin C levels elevated. Taken together, we disagree with the authors that cystatin C could be used as a marker of GFR in intensive care patients. Letter Cystatin C: unsuited to use as a marker of kidney function in the intensive care unit Raymond Wulkan 1 , Jan den Hollander 2 and Arie Berghout 2 1 Clinical Biochemist, Department of Clinical Chemistry, Hospital MCRZ, Rotterdam, The Netherlands 2 Consultant Physician, Department of Internal Medicine, Hospital MCRZ, Rotterdam, The Netherlands Corresponding author: Raymond Wulkan, WulkanR@mcrz.nl Published online: 10 May 2005 Critical Care 2005, 9:531-532 (DOI 10.1186/cc3541) This article is online at http://ccforum.com/content/9/5/531 © 2005 BioMed Central Ltd See related research by Villa et al., issue 9.2 [http://ccforum.com/content/9/2/R139] Authors’ response P Villa, M Jiménez, M-C Soriano, J Manzanares and P Casasnovas We read with interest the letter from Wulkan and coworkers about the use of cystatine C as a marker of glomerular filtration. The gold standard parameters for monitoring renal function are clearances of exogenous substances (inulin, [125]iothalamate, etc.), and in clinical practice the more extensively used markers of glomerular function, despite their limitations, are serum creatinine and creatinine clearance. In our opinion creatinine clearance represents a reasonably accurate and reliable estimate of GFR and is better than serum creatinine, at least in critically ill patients. Therefore, we compared serum cystatin C and serum creatinine with body surface corrected creatinine clearance. Morbidly obese patients were excluded from the study because of the possible perturbation in the calculation of body surface corrected creatinine clearance. In their letter, Wulkan and coworkers comment on the fact that we employed 80 ml/min per m 2 creatinine clearance as the cutoff point to identify renal dysfunction instead of the more generally accepted 50 ml/min per m 2 . Although 50 ml/min per m 2 is the more commonly used cutoff point, other studies [4,5] used a cutoff point of 84 ml/min per m 2 . We felt that it would be interesting to evaluate a more sensitive marker of early renal dysfunction in critically ill patients, and therefore we employed a cutoff point of 80 ml/min per m 2 in our study. In relation BioMed Central Page 1 of 8 (page number not for citation purposes) Chiropractic & Osteopathy Open Access Research Effects of body position on autonomic regulation of cardiovascular function in young, healthy adults Nobuhiro Watanabe* 1 , John Reece 2 and Barbara I Polus 1 Address: 1 Clinical Neuroscience Research Group, Division of Chiropractic, School of Health Sciences, RMIT University, Melbourne, Australia and 2 Division of Psychology, School of Health Sciences, RMIT University, Melbourne, Australia Email: Nobuhiro Watanabe* - s9812566@student.rmit.edu.au; John Reece - john.reece@rmit.edu.au; Barbara I Polus - barbara.polus@rmit.edu.au * Corresponding author Abstract Background: Analysis of rhythmic patterns embedded within beat-to-beat variations in heart rate (heart rate variability) is a tool used to assess the balance of cardiac autonomic nervous activity and may be predictive for prognosis of some medical conditions, such as myocardial infarction. It has also been used to evaluate the impact of manipulative therapeutics and body position on autonomic regulation of the cardiovascular system. However, few have compared cardiac autonomic activity in supine and prone positions, postures commonly assumed by patients in manual therapy. We intend to redress this deficiency. Methods: Heart rate, heart rate variability, and beat-to-beat blood pressure were measured in young, healthy non-smokers, during prone, supine, and sitting postures and with breathing paced at 0.25 Hz. Data were recorded for 5 minutes in each posture: Day 1 – prone and supine; Day 2 – prone and sitting. Paired t-tests or Wilcoxon signed-rank tests were used to evaluate posture- related differences in blood pressure, heart rate, and heart rate variability. Results: Prone versus supine: blood pressure and heart rate were significantly higher in the prone posture (p < 0.001). Prone versus sitting: blood pressure was higher and heart rate was lower in the prone posture (p < 0.05) and significant differences were found in some components of heart rate variability. Conclusion: Cardiac autonomic activity was not measurably different in prone and supine postures, but heart rate and blood pressure were. Although heart rate variability parameters indicated sympathetic dominance during sitting (supporting work of others), blood pressure was higher in the prone posture. These differences should be considered when autonomic regulation of cardiovascular function is studied in different postures. Background As body requirements change, autonomic output regu- lates cardiac function (e.g., heart rate), to maintain a sta- ble internal environment [1]. At first glance, the heart appears to beat regularly, however, the interval between one heartbeat and the next is not the same. Further, embedded within these beat-to-beat variations in length of interval between successive heartbeats are inherent rhythms, at specific frequencies. These changing frequen- cies constitute what are referred to, collectively, as heart Published: 28 November 2007 Chiropractic & Osteopathy 2007, 15:19 doi:10.1186/1746-1340-15-19 Received: 17 November 2006 Accepted: 28 November 2007 This article is available from: http://www.chiroandosteo.com/content/15/1/19 © 2007 Watanabe et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chiropractic & Osteopathy 2007, 15:19 http://www.chiroandosteo.com/content/15/1/19 Page 2 of 8 (page number not for citation purposes) rate variability (HRV) and can be revealed through power spectral analysis. The power spectrum characterises the strength (or power) of these frequencies and reflects sym- pathetic and parasympathetic (vagal) contributions to their generation. That is, a power spectral ... from 2/5 Endocrine Regulation of Kidney Function this family of hormones is atrial natriuretic hormone (ANH), a 28-amino acid peptide produced by heart atria in response to over-stretching of the... Ca++ levels are permitted Major Hormones That Influence GFR and RFB 3/5 Endocrine Regulation of Kidney Function Chapter Review Endocrine hormones act from a distance and paracrine hormones act locally.. .Endocrine Regulation of Kidney Function result, renin has an immediate effect on blood pressure due to angiotensin