Ergebnisse der Physiologie (REV PHYSIOL BIOCH P)

Publications in this journal

• Article: The Cardiomyocyte Cell Cycle in Hypertrophy, Tissue Homeostasis, and Regeneration.

  David C Zebrowski, Felix B Engel
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  ABSTRACT: Mammalian cardiomyocytes withdraw from the cell cycle shortly after birth. Although the adult heart is unable to regenerate, numerous reports have shown that adult cardiomyocytes exhibit a dynamic range of cell cycle activity under various physiological and pathological conditions. Reason and consequence of cardiomyocyte cell cycle activity remain unclear and have led to a number of misconceptions. Understanding the scenarios in which cycling happens may promote new perspectives on the differentiated state of cardiomyocytes, treatments for hypertrophy, heart regeneration and cancer therapy. In this review we discuss the result of cardiomyocyte cell cycle activity in aging and disease and studies manipulating cardiac cell cycle activity to promote cardiac regeneration. In addition, we focus on cardiomyocyte differentiation, cell cycle exit, and the relationship between ploidy and regenerative potential. Finally, we provide observations that may further advance the goal of inducing adult mammalian heart regeneration through cardiomyocyte proliferation.
  Ergebnisse der Physiologie 04/2013;
• Article: Spices: The Savory and Beneficial Science of Pungency.

  Bernd Nilius, Giovanni Appendino
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  ABSTRACT: Spicy food does not only provide an important hedonic input in daily life, but has also been anedoctically associated to beneficial effects on our health. In this context, the discovery of chemesthetic trigeminal receptors and their spicy ligands has provided the mechanistic basis and the pharmacological means to investigate this enticing possibility. This review discusses in molecular terms the connection between the neurophysiology of pungent spices and the "systemic" effects associated to their trigeminality. It commences with a cultural and historical overview on the Western fascination for spices, and, after analysing in detail the mechanisms underlying the trigeminality of food, the main dietary players from the transient receptor potential (TRP) family of cation channels are introduced, also discussing the "alien" distribution of taste receptors outside the oro-pharingeal cavity. The modulation of TRPV1 and TRPA1 by spices is next described, discussing how spicy sensations can be turned into hedonic pungency, and analyzing the mechanistic bases for the health benefits that have been associated to the consumption of spices. These include, in addition to a beneficial modulation of gastro-intestinal and cardio-vascular function, slimming, the optimization of skeletal muscle performance, the reduction of chronic inflammation, and the prevention of metabolic syndrome and diabetes. We conclude by reviewing the role of electrophilic spice constituents on cancer prevention in the light of their action on pro-inflammatory and pro-cancerogenic nuclear factors like NFκB, and on their interaction with the electrophile sensor protein Keap1 and the ensuing Nrf2-mediated transcriptional activity. Spicy compounds have a complex polypharmacology, and just like any other bioactive agent, show a balance of beneficial and bad actions. However, at least for moderate consumption, the balance seems definitely in favour of the positive side, suggesting that a spicy diet, a caveman-era technology, could be seriously considered in addition to caloric control and exercise as a measurement to prevent and control many chronic diseases associate to malnutrition from a Western diet.
  Ergebnisse der Physiologie 04/2013;
• Article: Chemosensory TRP Channels in the Respiratory Tract: Role in Toxic Lung Injury and Potential as "Sweet Spots" for Targeted Therapies.

  Thomas Büch, Eva Schäfer, Dirk Steinritz, Alexander Dietrich, Thomas Gudermann
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  ABSTRACT: Acute toxic lung injury by reactive inhalational compounds is an important and still unresolved medical problem. Hazardous gases or vapors, e. g. chlorine, phosgene, sulfur mustard or methyl isocyanate, are released during occupational accidents or combustion processes and also represent a potential threat in terroristic scenarios. According to their broad-range chemical reactivity, the mechanism of lung injury evoked by these agents has long been described as rather unspecific. Consequently, therapeutic options are still restricted to symptomatic treatment. However, in recent years, ion channels of the transient receptor potential (TRP) family have been identified to act as specific sensor molecules expressed in the respiratory tract and to engage defined signaling pathways upon inhalational exposure to toxic challenges. These pulmonary receptor molecules have been primarily characterized in sensory neurons of the lung. However, chemosensory molecules are also expressed in non-neuronal cells, e.g. in the lung epithelium as well as in the pulmonary vasculature. Thus, activation of respiratory chemosensors by toxic inhalants promotes a complex signaling network directly or indirectly regulating pulmonary blood flow, the integrity of the epithelial lining, and the mucociliary clearance of the bronchial system. This review gives a synopsis on reactive lung-toxic agents and their specific target molecules in the lung and summarizes the current knowledge about the pathophysiological role of chemosensory signaling in neuronal and non-neuronal cells in toxic lung injury. Finally, we describe possible future strategies for a causal, specifically tailored treatment option based on the mechanistic understanding of molecular events ensuing inhalation of lung-toxic agents.
  Ergebnisse der Physiologie 03/2013;
• Article: Pharmacological Inhibition of Actin Assembly to Target Tumor Cell Motility.

  Alexander Nürnberg, Alina Kollmannsperger, Robert Grosse
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  ABSTRACT: Tumor metastasis remains an unsolved clinical problem during treatment of malignant disease. Active cancer cell migration through extracellular matrices is an initial step in this process. Therefore, targeting dissemination and invasive motility of cancer cells from tumor lesions into surrounding tissues remains a pharmacological challenge. One of the initial critical steps during metastatic spread is the acquisition of cell invasive capabilities. It has become clear that this essentially involves deregulated actin reorganization and cytoskeletal dynamics in order to mobilize cell-cell contacts, acquire mesenchymal phenotypes, to drive mechanical force for stroma remodeling or to thrive through physical barriers such as basement membranes or vessel walls. Although the microtubule system has been targeted very successfully in the treatment of cancer, specific actin assembly and nucleation factors are just beginning to emerge as potential structures for selective pharmacological intervention. Here we summarize current research and successful approaches to chemically inhibit actin dynamics from a list of a growing number of identified actin nucleation and assembly factors, relevant for human disease.
  Ergebnisse der Physiologie 03/2013;
• Article: The Channel Physiology of the Skin.

  Attila Oláh, Attila Gábor Szöllősi, Tamás Bíró
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  ABSTRACT: During embryonic development, the skin, the largest organ of the human body, and nervous system are both derived from the neuroectoderm. Consequently, several key factors and mechanisms that influence and control central or peripheral nervous system activities are also present and hence involved in various regulatory mechanisms of the skin. Apparently, this is the case for the ion and non-ion selective channels as well. Therefore, in this review, we shall focus on delineating the regulatory roles of the channels in skin physiology and pathophysiology. First, we introduce key cutaneous functions and major characteristics of the channels in question. Then, we systematically detail the involvement of a multitude of channels in such skin processes (e.g. skin barrier formation, maintenance, and repair, immune mechanisms, exocrine secretion) which are mostly defined by cutaneous non-neuronal cell populations. Finally, we close by summarizing data suggesting that selected channels are also involved in skin diseases such as e.g. atopic dermatitis, psoriasis, non-melanoma cancers and malignant melanoma, genetic and autoimmune diseases, etc., as well as in skin ageing.
  Ergebnisse der Physiologie 11/2012;
• Article: TRPs in the Brain.

  Rudi Vennekens, Aurelie Menigoz, Bernd Nilius
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  ABSTRACT: The Transient receptor potential (TRP) family of cation channels is a large protein family, which is mainly structurally uniform. Proteins consist typically of six transmembrane domains and mostly four subunits are necessary to form a functional channel. Apart from this, TRP channels display a wide variety of activation mechanisms (ligand binding, G-protein coupled receptor dependent, physical stimuli such as temperature, pressure, etc.) and ion selectivity profiles (from highly Ca(2+) selective to non-selective for cations). They have been described now in almost every tissue of the body, including peripheral and central neurons. Especially in the sensory nervous system the role of several TRP channels is already described on a detailed level. This review summarizes data that is currently available on their role in the central nervous system. TRP channels are involved in neurogenesis and brain development, synaptic transmission and they play a key role in the development of several neurological diseases.
  Ergebnisse der Physiologie 11/2012;
• Article: Induced Pluripotent Stem Cells in Cardiovascular Research.

  Daniel Sinnecker, Ralf J Dirschinger, Alexander Goedel, Alessandra Moretti, Peter Lipp, Karl-Ludwig Laugwitz
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  ABSTRACT: The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSC) by overexpression of a combination of transcription factors bears the potential to spawn a wealth of new applications in both preclinical and clinical cardiovascular research. Disease modeling, which is accomplished by deriving iPSC lines from patients affected by heritable diseases and then studying the pathophysiology of the diseases in somatic cells differentiated from these patient-specific iPSC lines, is the so far most advanced of these applications. Long-QT syndrome and catecholaminergic polymorphic ventricular tachycardia are two heart rhythm disorders that have been already successfully modeled by several groups using this approach, which will likely serve to model other mono- or polygenetic cardiovascular disorders in the future. Test systems based on cells derived from iPSC might prove beneficial to screen for novel cardiovascular drugs or unwanted drug side effects and to individualize medical therapy. The application of iPSC for cell therapy of cardiovascular disorders, albeit promising, will only become feasible if the problem of biological safety of these cells will be mastered.
  Ergebnisse der Physiologie 03/2012;
• Article: Quantifying and Modeling the Temperature-Dependent Gating of TRP Channels.

  Thomas Voets
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  ABSTRACT: The ability to sense environmental temperatures and to avoid noxious heat or cold is crucial for the survival of all organisms. In mammals, sensory neurons from dorsal root and trigeminal ganglia convey thermal information from the skin, mouth and nose to the central nervous system. Recent evidence has established that thermoTRPs, a subset of the TRP superfamily of cation channels, act as primary temperature sensors in cold- and heat-sensitive neurons. The gating of these thermoTRPs exhibits strong temperature dependence, leading to steep changes in inward current upon heating or cooling. The origin of this striking temperature sensitivity remains incompletely understood. In this review, I propose criteria that define a thermoTRP, analyse the usefulness and limitations of the commonly used parameters thermal threshold and Q ( 10 ), provide an overview of possible thermodynamic principles and gating schemes for thermosensitive TRP channels, and perform a meta-analysis of published work on the molecular basis of the heat sensitivity in TRPV1. This review may form a useful reference for the analysis and interpretation of further biophysical and structure-function studies dissecting the molecular basis of thermosensitivity in TRP channels.
  Ergebnisse der Physiologie 02/2012;
• Article: Regulation of renin release by local and systemic factors.

  F Schweda, A Kurtz
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  ABSTRACT: The renin-angiotensin system (RAS) is critically involved in the regulation of the salt and volume status of the body and blood pressure. The activity of the RAS is controlled by the protease renin, which is released from the renal juxtaglomerular epithelioid cells into the circulation. Renin release is regulated in negative feedback-loops by blood pressure, salt intake, and angiotensin II. Moreover, sympathetic nerves and renal autacoids such as prostaglandins and nitric oxide stimulate renin secretion. Despite numerous studies there remained substantial gaps in the understanding of the control of renin release at the organ or cellular level. Some of these gaps have been closed in the last years by means of gene-targeted mice and advanced imaging and electrophysiological methods. In our review, we discuss these recent advances together with the relevant previous literature on the regulation of renin release.
  Ergebnisse der Physiologie 01/2012; 161:1-44.
• Article: Shaping membranes for endocytosis.

  M Krauss, V Haucke
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  ABSTRACT: Endocytosis is essential for virtually all eukaryotic cells to internalize nutrients, antigens, pathogens, and cell surface receptors from the plasma membrane into membrane-bounded, endocytic vesicles to regulate cell homeostasis, cell signaling, and development. Distinct mechanisms mediate endocytic uptake of a large variety of distinctly sized cargoes ranging from small molecules to viruses or bacteria. Common to all of these endocytic pathways is the deformation of the plasma membrane by intracellular factors including scaffolding proteins, amphipathic peripheral membrane proteins, and lipid-modifying enzymes. In this review we summarize how different cargoes exploit distinct pathways for cell entry, and how proteins assist the generation of curved membrane domains during internalization.
  Ergebnisse der Physiologie 01/2012; 161:45-66.
• Article: Intrinsically photosensitive retinal ganglion cells.

  Gary E Pickard, Patricia J Sollars
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  ABSTRACT: Intrinsically photosensitive retinal ganglion cells (ipRGCs) respond to light in the absence of all rod and cone photoreceptor input. The existence of these ganglion cell photoreceptors, although predicted from observations scattered over many decades, was not established until it was shown that a novel photopigment, melanopsin, was expressed in retinal ganglion cells of rodents and primates. Phototransduction in mammalian ipRGCs more closely resembles that of invertebrate than vertebrate photoreceptors and appears to be mediated by transient receptor potential channels. In the retina, ipRGCs provide excitatory drive to dopaminergic amacrine cells and ipRGCs are coupled to GABAergic amacrine cells via gap junctions. Several subtypes of ipRGC have been identified in rodents based on their morphology, physiology and expression of molecular markers. ipRGCs convey irradiance information centrally via the optic nerve to influence several functions including photoentrainment of the biological clock located in the hypothalamus, the pupillary light reflex, sleep and perhaps some aspects of vision. In addition, ipRGCs may also contribute irradiance signals that interface directly with the autonomic nervous system to regulate rhythmic gene activity in major organs of the body. Here we review the early work that provided the motivation for searching for a new mammalian photoreceptor, the ground-breaking discoveries, current progress that continues to reveal the unusual properties of these neuron photoreceptors, and directions for future investigation.
  Ergebnisse der Physiologie 12/2011; 162:59-90.
• Article: Cardiac ion channels and mechanisms for protection against atrial fibrillation.

  Morten Grunnet, Bo Hjorth Bentzen, Ulrik Svane Sørensen, Jonas Goldin Diness
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  ABSTRACT: Atrial fibrillation (AF) is recognised as the most common sustained cardiac arrhythmia in clinical practice. Ongoing drug development is aiming at obtaining atrial specific effects in order to prevent pro-arrhythmic, devastating ventricular effects. In principle, this is possible due to a different ion channel composition in the atria and ventricles. The present text will review the aetiology of arrhythmias with focus on AF and include a description of cardiac ion channels. Channels that constitute potentially atria-selective targets will be described in details. Specific focus is addressed to the recent discovery that Ca(2+)-activated small conductance K(+) channels (SK channels) are important for the repolarisation of atrial action potentials. Finally, an overview of current pharmacological treatment of AF is included.
  Ergebnisse der Physiologie 10/2011; 162:1-58.
• Article: Transient receptor potential cation channels in pancreatic β cells.

  Barbara Colsoul, Rudi Vennekens, Bernd Nilius
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  ABSTRACT: There is now overwhelming evidence that TRP channels might play a significant role in the regulation of insulin release from pancreatic β cells, which is until now insufficiently recognized. TRP channels are abundantly expressed on β cells. The focus of this review will be on cation channels from the melastatin TRP -subfamily. We will discuss how TRPM channels can influence Ca(2+) signaling in β cells. Knock out models of TRPM2 and TRPM5, which show a pre-diabetic phenotype, will be illustrative for this purpose. Based on these insights, TRPM5 will be critically evaluated as a potential drug target for diabetes type II therapy, which has received currently a high interest of the pharmaceutical industry. In addition, an unexpected role of the TRP channel TRPM3 as a gatekeeper of zinc, which is required for insulin storage, will be considered. Finally, we will critically discuss the use of mouse models for the unraveling of basic mechanisms of insulin release. The study of the role of TRP channels in the regulation of insulin release is of wide interest for fundamental research, evaluation of molecular mechanisms of disease and exploration of novel drug targets for metabolic diseases.
  Ergebnisse der Physiologie 07/2011; 161:87-110.
• Article: The long journey: actin on the road to pro- and eukaryotic cells.

  Brigitte M Jockusch, Peter L Graumann
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  ABSTRACT: Actin-like proteins comprise a large group of polymorphic proteins that readily form filaments engaged in cytoskeletal functions. Various members have been identified in prokaryotic and eukaryotic cells, e.g. MreB, ParM and Ta0583, and actin and the actin-related proteins, ARPs, respectively. Therefore, it is assumed that an ancestor of actin/MreB/ParM already existed in the last common progenitor of all cells. In eubacteria and archaea, actin-like proteins are either membrane-associated or freely soluble, and their activities are related to motility, cell shape maintenance, subcellular organization and cell cycle progression. In eukaryotes, all these functions are executed by actin in various isoforms. Additional functions have been described for actin and ARPs in the nucleus of the eukaryotic cell, and some of those were also discovered in prokaryotes. In the current essay, we compare structures and selected functions of prokaryotic and eukaryotic actins and discuss various aspects on how actins may have found their way into bacteria, into the eukaryotic cytoplasm and into the nuclear compartment.
  Ergebnisse der Physiologie 06/2011; 161:67-85.
• Article: Lipid homeostasis in macrophages - implications for atherosclerosis.

  G Schmitz, M Grandl
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  ABSTRACT: In industrialized societies with excess food supply, obesity is an expanding problem. As a result of metabolic overload, besides obesity, insulin resistance, type-2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together make up the metabolic syndrome. The imbalance of lipid uptake, metabolism, and removal in many organs such as the liver, muscle, adipose tissue, vessel wall, and macrophages triggers organ transdifferentiation toward lipid storage phenotypes. Macrophages, foam cells, and osteoclasts in calcifying lesions are a hallmark of atherosclerosis and the metabolic syndrome, and must be regarded as an important therapeutic target. In this review, pathways regulating lipid homeostasis in macrophages are updated. These include lipid influx through different receptor entry pathways, the role of membrane microdomains, endolysosomal and cytosolic lipid storage leading to phospholipidosis, and lipid droplet accumulation or activation of lipid efflux either through the Golgi system or bypassing this organelle on the way to the plasma membrane. The interdependence of these pathways and pharmacological modifications are described. The monocyte innate immunity receptor complex in defining monocyte subpopulations and their role in cardiovascular disease is taken into account. The composition of certain molecular lipid species in membrane microdomains and other organelles is essential for cellular functions affecting raft dynamics, signal transduction, and membrane and organelle trafficking. It is very likely that the underlying defects in lipid-associated rare genetic diseases such as ABCA1 deficiency, Niemann-Pick disease type C, as well as the more frequent complex disorders associated with atherosclerosis and phospholipidosis are related to disturbances in membrane homeostasis, signal transduction, and cellular lipid metabolism.
  Ergebnisse der Physiologie 02/2008; 160:93-125.
• Article: Endocannabinoids: synthesis and degradation.

  V Di Marzo
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  ABSTRACT: Endocannabinoids were defined in 1995 as endogenous agonists of cannabinoid receptors, i.e. of the G protein-coupled receptors for cannabis's psychoactive principle, Delta9-tetrahydrocannabinol. Although there appear to be several endocannabinoids, only two of such endogenous mediators have been thoroughly studied so far: anandamide and 2-arachidonoylglycerol (2-AG). A general strategy seems to apply to the biosynthesis and degradation of anandamide and 2-AG, although the levels of these two compounds appear to be regulated in different, and sometimes even opposing, ways. "Endocannabinoid enzymes", that is to say enzymes that catalyse endocannabinoid biosynthesis or degradation, have been identified and in some cases cloned, and will be described in this review together with their possible pharmacological targeting for therapeutic purposes. The cellular and subcellular localization and the modes for the regulation of the expression and activity of these enzymes play an important role in the functions played by the endocannabinoids under physiological and pathological conditions.
  Ergebnisse der Physiologie 02/2008; 160:1-24.
• Article: Lipoxins: update and impact of endogenous pro-resolution lipid mediators.

  S J O'Meara, K Rodgers, C Godson
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  ABSTRACT: Lipoxins (LXs) are endogenously produced eicosanoids that are typically generated by transcellular biosynthesis. These trihydroxytetraene-containing lipid mediators and their stable synthetic analogues possess a wide spectrum of anti-inflammatory and pro-resolution bioactions both in vitro and in vivo. More recently, LXs have emerged as potential anti-fibrotic mediators that may influence pro-fibrotic cytokines and matrix-associated gene expression in response to platelet-derived growth factor (PDGF). Here we review the biosynthesis, metabolism and bioactions of LXs and LX analogues and their therapeutic potential.
  Ergebnisse der Physiologie 02/2008; 160:47-70.
• Article: Biological effects of lysophospholipids.

  R Rivera, J Chun
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  ABSTRACT: Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are potent biologically active lipid mediators that exert a wide range of cellular effects through specific G protein-coupled receptors. To date, four LPA receptors and five S1P receptors have been identified. These receptors are expressed in a large number of tissues and cell types, allowing for a wide variety of cellular responses to lysophospholipid signaling, including cell adhesion, cell motility, cytoskeletal changes, proliferation, angiogenesis, process retraction, and cell survival. In addition, recent studies in mice show that specific lysophospholipid receptors are required for proper cardiovascular, immune, respiratory, and reproductive system development and function. Lysophospholipid receptors may also have specific roles in cancer and other diseases. This review will cover identification and expression of the lysophospholipid receptors, as well as receptor signaling properties and function. Additionally, phenotypes of mice deficient for specific lysophospholipid receptors will be discussed to demonstrate how these animals have furthered our understanding of the role lysophospholipids play in normal biology and disease.
  Ergebnisse der Physiologie 02/2008; 160:25-46.
• Article: Multi-photon excitation imaging of dynamic processes in living cells and tissues.

  R K P Benninger, M Hao, D W Piston
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  ABSTRACT: Over the past decade, two-photon microscopy has successfully made the transition from the laser laboratory into a true biological research setting. This has been due in part to the recent development of turnkey ultrafast laser systems required for two-photon microscopy, allowing ease of use in nonspecialist laboratories. The advantages of two-photon microscopy over conventional optical sectioning techniques are for greater imaging depths and reduced overall phototoxicity, as such enabling noninvasive intra-vital imaging of cellular and subcellular processes. Greater understanding of these advantages has allowed this technique to be more effectively utilized in a biological research setting. This review will cover the recent widespread uses of two-photon microscopy and highlight the wide range of physiological studies enabled in fields such as neurosciences, developmental biology, immunology, cancer biology, and endocrinology.
  Ergebnisse der Physiologie 02/2008; 160:71-92.