Showing papers in "Physiology in 2007"
TL;DR: This review will examine UPR signaling that results in cell protective responses, as well as the mechanisms leading to apoptosis induction, which can lead to pathological states due to chronic ER stress.
Abstract: The endoplasmic reticulum (ER) is the cellular site of newly synthesized secretory and membrane proteins. Such proteins must be properly folded and posttranslationally modified before exit from the organelle. Proper protein folding and modification requires molecular chaperone proteins as well as an ER environment conducive for these reactions. When ER lumenal conditions are altered or chaperone capacity is overwhelmed, the cell activates signaling cascades that attempt to deal with the altered conditions and restore a favorable folding environment. Such alterations are referred to as ER stress, and the response activated is the unfolded protein response (UPR). When the UPR is perturbed or not sufficient to deal with the stress conditions, apoptotic cell death is initiated. This review will examine UPR signaling that results in cell protective responses, as well as the mechanisms leading to apoptosis induction, which can lead to pathological states due to chronic ER stress.
474 citations
TL;DR: Neuronal circuits in the central nervous system play a critical role in orchestrating the control of glucose and energy homeostasis and converge to the hypothalamus to cooperate with leptin and insulin in controlling the melanocortin pathway.
Abstract: Neuronal circuits in the central nervous system play a critical role in orchestrating the control of glucose and energy homeostasis. Glucose, beside being a nutrient, is also a signal detected by several glucose-sensing units that are located at different anatomical sites and converge to the hypothalamus to cooperate with leptin and insulin in controlling the melanocortin pathway.
325 citations
TL;DR: This work has proposed the ATP-switch model for function in which the paired nucleotide binding domains switch between an ATP-dependent closed conformation and a nucleotide-free, open conformation to drive the translocation of ligand.
Abstract: ATP binding cassette transporters are ubiquitous integral membrane proteins that actively transport ligands across biological membranes, a process critical for most aspects of cell physiology. These proteins are important clinically and economically. Their dysfunction underlies a number of human genetic diseases, and the ability of some to pump cytotoxic molecules from cells confers resistance to antibiotics, herbicides, and chemotherapeutic drugs. Recent structure analyses interpreted in light of a large body of biochemistry has resulted in the ATP-switch model for function in which the paired nucleotide binding domains switch between an ATP-dependent closed conformation and a nucleotide-free, open conformation to drive the translocation of ligand.
302 citations
TL;DR: The evidence for an important role for the microcirculation as a possible link between obesity, insulin resistance and hypertension is reviewed.
Abstract: Obesity is an important risk factor for insulin resistance and hypertension and plays a central role in the metabolic syndrome. Insight into the pathophysiology of this syndrome may lead to new treatments. This paper has reviewed the evidence for an important role for the microcirculation as a possible link between obesity, insulin resistance and hypertension.
276 citations
TL;DR: A variety of fiber types with different contractile and metabolic properties is present in mammalian skeletal muscle, whose identification may provide potential therapeutic targets for the prevention and treatment of metabolic and neuromuscular diseases.
Abstract: A variety of fiber types with different contractile and metabolic properties is present in mammalian skeletal muscle. The fiber-type profile is controlled by nerve activity via specific signaling pathways, whose identification may provide potential therapeutic targets for the prevention and treatment of metabolic and neuromuscular diseases.
256 citations
TL;DR: Bonen and Chabowski as discussed by the authors proposed a method for the identification of biomarkers of cancer in the human brain and showed that the method can be used to diagnose cancer in humans.
Abstract: ![Figure][1]
Arend Bonen Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Ontario, Canada abonen{at}uoguelph.ca
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Adrian Chabowski Department of Physiology, Medical University of Bialystok, Bialystok, Poland
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238 citations
TL;DR: Design principles, current modeling predictions, and examples of pH sensors or proteins that have activities or ligand-binding affinities that are regulated by changes in intracellular pH are presented.
Abstract: Changes in intracellular pH regulate many cell behaviors, including proliferation, migration, and transformation. However, our understanding of how physiological changes in pH affect protein conformations and macromolecular assemblies is limited. We present design principles, current modeling predictions, and examples of pH sensors or proteins that have activities or ligand-binding affinities that are regulated by changes in intracellular pH.
235 citations
TL;DR: Inputs from various cell-signaling events can impact β-catenin function, which may be necessary for the finely tuned adhesive and signaling responses required for tissue morphogenesis.
Abstract: β-Catenin plays a critical structural role in cadherin-based adhesions and is also an essential co-activator of Wnt-mediated gene expression. The degree to which β-catenin participates in these two functions is dictated by the availability of β-catenin binding partners, and an emerging theme is that these binding interactions are regulated by phosphorylation. Inputs from various cell-signaling events can therefore impact β-catenin function, which may be necessary for the finely tuned adhesive and signaling responses required for tissue morphogenesis.
231 citations
TL;DR: Traditional and novel mechanisms relating hypertrophy and heart failure are described at the physiological, cellular, and molecular levels and the rational application of these mechanistic considerations to therapeutics targeting hypertropy andheart failure is discussed.
Abstract: Cardiac hypertrophy leads to heart failure, and both conditions can ultimately prove lethal. Here, traditional and novel mechanisms relating hypertrophy and heart failure are described at the physiological, cellular, and molecular levels. The rational application of these mechanistic considerations to therapeutics targeting hypertrophy and heart failure is discussed.
221 citations
TL;DR: This review examines some new hypotheses related to the structure and function of these proteins, many of which have widely varying substrate specificity, kinetic behavior, and tissue distribution.
Abstract: The recent sequencing of the human genome has resulted in the addition of nine new hGLUT isoforms to the SLC2A family, many of which have widely varying substrate specificity, kinetic behavior, and tissue distribution. This review examines some new hypotheses related to the structure and function of these proteins.
217 citations
TL;DR: Basic aspects of in vivo calcium imaging are discussed and recent developments that will help to uncover operating principles of neural circuits are highlighted.
Abstract: Spatiotemporal activity patterns in local neural networks are fundamental to brain function. Network activity can now be measured in vivo using two-photon imaging of cell populations that are labeled with fluorescent calcium indicators. In this review, we discuss basic aspects of in vivo calcium imaging and highlight recent developments that will help to uncover operating principles of neural circuits.
TL;DR: The sweat gland has played a foremost role in diagnosing, defining pathophysiology, debunking misconceptions, and increasing the authors' understanding of the effects of the disease on organs, tissues, cells, and molecules.
Abstract: Lessons from the sweat gland on cystic fibrosis (CF) began long before modern medicine became a science. In European folklore, the curse that "a child that taste salty when kissed will soon die" (Alonso y de los Ruyzes de Fonteca J. Diez Previlegios para Mugeres Prenadas. Henares, Spain, 1606) has been taken by many as a direct reference to cystic fibrosis [Busch R. Acta Univ Carol Med (Praha) 36: 13-15, 1990]. The high salt concentration in sweat from patients with CF is now accepted as almost pathognomonic with this fatal genetic disease, but the earliest descriptions of cystic fibrosis as a disease entity did not mention sweat or sweat glands (Andersen DH. Am J Dis Child 56: 344-399, 1938; Andersen DH, Hodges RG. Am J Dis Child 72: 62-80, 1946). Nonetheless, defective sweating soon became an inseparable, and major, component of the constellation of symptoms that diagnose "cystic fibrosis" (Davis PB. Am J Respir Crit Care Med 173: 475-482, 2006). The sweat gland has played a foremost role in diagnosing, defining pathophysiology, debunking misconceptions, and increasing our understanding of the effects of the disease on organs, tissues, cells, and molecules. The sweat gland has taught us much.
TL;DR: The implications of the use of the vibration sense as a multimodal signal will be discussed in light of the elephant's overall fitness and survival.
Abstract: This review explores the mechanisms that elephants may use to send and receive seismic signals from a physical, anatomical, behavioral, and physiological perspective. The implications of the use of the vibration sense as a multimodal signal will be discussed in light of the elephant's overall fitness and survival.
TL;DR: The role of wallShear stress in the chicken embryonic heart is analyzed to determine its effect on cardiac development through regulating gene expression and a set of endothelial shear stress-responsive genes coding for endothelin-1, lung Krüppel-like factor, and endothelial nitric oxide synthase are specifically addressed.
Abstract: In this review, the role of wall shear stress in the chicken embryonic heart is analyzed to determine its effect on cardiac development through regulating gene expression. Therefore, background information is provided for fluid dynamics, normal chicken and human heart development, cardiac malformations, cardiac and vitelline blood flow, and a chicken model to induce cardiovascular anomalies. A set of endothelial shear stress-responsive genes coding for endothelin-1 (ET-1), lung Kruppel-like factor (LKLF/KLF2), and endothelial nitric oxide synthase (eNOS/NOS-3) are active in development and are specifically addressed.
TL;DR: This work has shown that mitochondria have privileged access to cytoplasmic Ca(2+) without requiring a direct communication with the endoplasmic reticulum.
Abstract: Mitochondria have a low affinity for Ca2+, but they take up these ions during normal cell activity because they are in close proximity to the sites of calcium entry into the cell and of internal Ca...
TL;DR: Results from behavioral studies with lesion of the direct pathway suggest that the indirect CM pathway can mediate the command for dexterous finger movements.
Abstract: Recent studies from our group have demonstrated the existence of a disynaptic excitatory cortico-motoneuronal (CM) pathway in macaque monkeys via propriospinal neurons in the midcervical segments. Results from behavioral studies with lesion of the direct pathway suggest that the indirect CM pathway can mediate the command for dexterous finger movements.
TL;DR: The coordinated sequence of membrane trafficking events required for phagocytosis involves multiple organelles and also serves other cellular functions, such as cytokine secretion.
Abstract: Phagocytosis is essential for the elimination of pathogens and for clearance of apoptotic bodies. The ingestion process entails extensive remodeling of the cellular membranes, particularly when large and/or multiple particles are engulfed. The membrane fusion and fission events that accompany phagocytosis are described. The coordinated sequence of membrane trafficking events required for phagocytosis involves multiple organelles and also serves other cellular functions, such as cytokine secretion.
TL;DR: The mechanism of free fatty acid (FFA) and its role in inflammation, injury and wound healing are studied.
Abstract: ![Figure][1]
J. Patrick Kampf Torrey Pines Institute for Molecular Studies, San Diego, California
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Alan M. Kleinfeld Torrey Pines Institute for Molecular Studies, San Diego, California akleinfeld{at}tpims.org
The mechanism of free fatty acid (FFA)
TL;DR: Emerging evidence that transport of these signaling molecules across the plasma membrane allows them to be recycled as "third messengers," extending their ability to convey information in a domain outside the cell.
Abstract: Calcium and cyclic AMP are familiar second messengers that typically become elevated inside cells on activation of cell surface receptors. This article will explore emerging evidence that transport of these signaling molecules across the plasma membrane allows them to be recycled as “third messengers,” extending their ability to convey information in a domain outside the cell.
TL;DR: The current understanding of the inherited renal acidoses at a genetic and molecular level is reviewed.
Abstract: Inherited acidosis may result from a primary renal defect in acid-base handling, emphasizing the central role of the kidney in control of body pH; as a secondary phenomenon resulting from abnormal renal electrolyte handling; or from excess production of acid elsewhere in the body. Here, we review our current understanding of the inherited renal acidoses at a genetic and molecular level.
TL;DR: Current knowledge about the transverse tubules of mammalian cardiac ventricular myocytes are reviewed, focusing on Ca2+ signaling and changes observed in pathological conditions.
Abstract: The transverse tubules of mammalian cardiac ventricular myocytes are invaginations of the surface membrane. Recent data have revealed that their structure and function are more complex than previously believed. Here, we review current knowledge about their role in cardiac function, focusing on Ca2+ signaling and changes observed in pathological conditions.
TL;DR: Current concepts of how these relatively under-appreciated actions of molecular motors are responsible for modulation of the ejection time and isovolumic relaxation in the beating heart are discussed.
Abstract: Molecular motors housed in myosins of the thick filament react with thin-filament actins and promote force and shortening in the sarcomeres. However, other actions of these motors sustain sarcomeric activation by cooperative feedback mechanisms in which the actin-myosin interaction promotes thin-filament activation. Mechanical feedback also affects the actin-myosin interaction. We discuss current concepts of how these relatively under-appreciated actions of molecular motors are responsible for modulation of the ejection time and isovolumic relaxation in the beating heart.
TL;DR: Temporal and spatial regulation of PKA activity are essential for vigorous sperm motility and for the resumption of meiosis in oocytes, two events required for successful fertilization.
Abstract: Temporal and spatial regulation of PKA activity are essential for vigorous sperm motility and for the resumption of meiosis in oocytes, two events required for successful fertilization. Genetic mutations in mice that affect PKA signaling in germ cells lead to infertility and illustrate the importance of this pathway in mammalian reproduction.
TL;DR: The role of matrix metalloproteonases (MMPs) in the gut in health, in gut inflammation, and in cancer is reviewed.
Abstract: The gastrointestinal mucosa is an extremely soft, highly vascularised tissue, with a single layer of epithelium separating the gut lumen from the host. Epithelial cells adhere to a thin basement membrane that is produced by both epithelial cells and the underlying stromal cells. Signals passing between epithelial cells and stromal cells are needed for normal gut structure. In gut diseases, however, epithelial cells and stromal cells produce large amounts of matrix degrading enzymes (matrix metalloproteinases), the function of which is only beginning to be elucidated. Here, we review the role of matrix metalloproteonases (MMPs) in the gut in health, in gut inflammation, and in cancer.
TL;DR: Delivery of SNOs by the RBC can be harnessed for therapeutic gain, and early results support the logic of this approach in the treatment of diseases as varied as cancer and neonatal pulmonary hypertension.
Abstract: The biology of NO (nitric oxide) is poorly explained by the activity of the free radical NO ((.)NO) itself. Although (.)NO acts in an autocrine and paracrine manner, it is also in chemical equilibrium with other NO species that constitute stable stores of NO bioactivity. Among these species, S-nitrosylated hemoglobin (S-nitrosohemoglobin; SNO-Hb) is an evolved transducer of NO bioactivity that acts in a responsive and exquisitely regulated manner to control cardiopulmonary and vascular homeostasis. In SNO-Hb, O(2) sensing is dynamically coupled to formation and release of vasodilating SNOs, endowing the red blood cell (RBC) with the capacity to regulate its own principal function, O(2) delivery, via regulation of blood flow. Analogous, physiological actions of RBC SNO-Hb also contribute to central nervous responses to blood hypoxia, the uptake of O(2) from the lung to blood, and baroreceptor-mediated control of the systemic flow of blood. Dysregulation of the formation, export, or actions of RBC-derived SNOs has been implicated in human diseases including sepsis, sickle cell anemia, pulmonary arterial hypertension, and diabetes mellitus. Delivery of SNOs by the RBC can be harnessed for therapeutic gain, and early results support the logic of this approach in the treatment of diseases as varied as cancer and neonatal pulmonary hypertension.
TL;DR: A review of the principles of signal detection of all-or-none events in noisy single-trial data is illustrated, using as an example action potential recording with optical voltage reporters.
Abstract: Optical imaging of physiological events in real time can yield insights into biological function that would be difficult to obtain by other experimental means. However, the detection of all-or-none events, such as action potentials or vesicle fusion events, in noisy single-trial data often requires a careful balance of tradeoffs. The analysis of such experiments, as well as the design of optical reporters and instrumentation for them, is aided by an understanding of the principles of signal detection. This review illustrates these principles, using as an example action potential recording with optical voltage reporters.
TL;DR: The gastric H+-K+-ATPase pumps H+ into the lumen and takes up K+ in parallel and inactivation of KCNE2/KCNQ1 channels abrogates gastric acid secretion and dramatically modifies the architecture of gastric mucosa.
Abstract: The gastric H+-K+-ATPase pumps H+ into the lumen and takes up K+ in parallel. In the acid-producing parietal cells, luminal KCNE2/KCNQ1 K+ channels play a pivotal role in replenishing K+ in the luminal fluid. Inactivation of KCNE2/KCNQ1 channels abrogates gastric acid secretion and dramatically modifies the architecture of gastric mucosa.
TL;DR: Exocytosis of insulin-containing secretory vesicles in pancreatic beta-cells is crucial to maintenance of plasma glucose levels and mechanisms in beta- cells at the single-vesicle level are discussed.
Abstract: Exocytosis of insulin-containing secretory vesicles in pancreatic β-cells is crucial to maintenance of plasma glucose levels. They fuse with the plasma membrane in a regulated manner to release their contents and are subsequently recaptured either intact or through conventional clathrin-mediated endocytosis. Here, we discuss these mechanisms in β-cells at the single-vesicle level.
TL;DR: Advances in the understanding of the molecular basis of conditions such as heart failure, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within reach of gene-based therapy.
Abstract: Heart failure is a major cause of morbidity and mortality in contemporary societies. Although progress in conventional treatment modalities is making steady and incremental gains to reduce this disease burden, there remains a need to explore new and potentially therapeutic approaches. Gene therapy, for example, was initially envisioned as a treatment strategy for inherited monogenic disorders. It is now apparent that gene therapy has broader potential that also includes acquired polygenic diseases, such as heart failure. Advances in the understanding of the molecular basis of conditions such as these, together with the evolution of increasingly efficient gene transfer technology, has placed congestive heart failure within reach of gene-based therapy.
TL;DR: The inner ear contains delicate sensory receptors that have adapted to detect the minutest mechanical disturbances and are implicated in all steps of the transduction process, as well as in its regulation by an impressive ensemble of finely tuned feedback control mechanisms.
Abstract: The inner ear contains delicate sensory receptors that have adapted to detect the minutest mechanical disturbances. Ca2+ ions are implicated in all steps of the transduction process, as well as in its regulation by an impressive ensemble of finely tuned feedback control mechanisms. Recent studies have unveiled some of the key players, but things do not sound quite right yet.