bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular Virus Trafficking Reveals Physiological Characteristics of the Cytoskeleton
Authors: Stidwill Robert P. , Greber Urs F.
Published: December 2017

Virus particles that infect eukaryotic cells can take advantage of the cytoskeleton and associated motors to translocate through the cytoplasm. Depending on the virus, motor proteins are recruited or, alternatively, cytoskeletal elements are induced to polymerize onto viral structures. Here we review recent advances toward understanding the roles of the cytoskeleton in virus trafficking.
Atrial Natriuretic Peptide: Regulator of Chronic Arterial Blood Pressure
Authors: Melo Luis Gabriel , Pang Stephen C. , Ackermann Uwe
Published: December 2017

Recent findings in atrial natriuretic peptide (ANP) transgenic and gene knockout mouse models uncovered a tonic vasodilatory effect of this hormone that contributes to chronic blood pressure homeostasis. With elevated salt intake, ANP-mediated antagonism of the renin-angiotensin system is essential for blood pressure constancy, suggesting that a deficiency in ANP activity may underlie the etiology of sodium-retaining disorders.
Role of Nitric Oxide in Buffering Short-Term Blood Pressure Fluctuations
Authors: Stauss Harald M. , Persson Pontus B.
Published: December 2017

Blood pressure instability may promote cardiovascular morbidity. Recent data suggest a role of nitric oxide in stabilizing arterial blood pressure. A rise in blood pressure enhances endothelial shear stress and nitric oxide release. The resulting vasodilation antagonizes the initial increase in blood pressure. This system can respond within 2–10 seconds.
Neurophysiology of Spatial Cognition
Authors: Bures Jan , Fenton André A.
Published: December 2017

Understanding of the neurophysiology of cognition is advancing through the study of how animals navigate and understand space. Manipulating various classes of spatial information and recording from hippocampal neurons provides a robust model for understanding how the brain stores and constructs the spatial memories that are critical for organizing daily experience.
Urocortin: A Novel Player in Cardiac Control
Authors: Parkes David G. , May Clive N.
Published: December 2017

Urocortin is a potent regulator of cardiac function, with actions that are prolonged in experimental animals. These changes are mediated via binding to corticotropin-releasing factor receptors found in peripheral tissues. The effects of urocortin on behavior, appetite, inflammation, and the cardiovascular system suggest that this peptide may be an endogenous factor mediating actions previously attributed to corticotropin-releasing factor.
Cation-Chloride Cotransporters in Neuronal Communication
Authors: Delpire E.
Published: December 2017

Two isoforms of the cation-Cl– cotransporter family are expressed in neurons and modulate neurotransmission. NKCC1, a Na+-K+-2Cl– cotransporter, by raising internal Cl–, is responsible for excitatory GABAergic activity in immature brain and in adult sensory neurons. KCC2, a neuronal-specific isoform of the K+-Cl– cotransporter, by lowering internal Cl–, is critical for inhibitory GABA responses in mature central nervous system neurons.
Neutrophil Diapedesis: Paracellular or Transcellular?
Authors: Kvietys Peter R. , Sandig Martin
Published: December 2017

To reach an inflammatory site in the interstitium, circulating neutrophils (PMN) must first traverse the endothelial barrier. Whether PMN emigrate between endothelial cells (paracellular pathway) or through the endothelial cells proper (transcellular pathway) is controversial. Herein, we present anatomic, functional, and teleological arguments that support both points of view. An attempt is also made to reconcile this apparent controversy.
Calcium, Cross-Bridges, and the Frank-Starling Relationship
Authors: Fuchs Franklin , Smith Stephen H.
Published: December 2017

The steep relationship between active force and length in cardiac muscle is based on a length dependence of myofilament Ca2+ sensitivity. However, it is not muscle length but the lateral spacing between actin and myosin filaments that sets the level of Ca2+ sensitivity, mainly through modulation of myosin-mediated activation of the thin filament.
Leukocyte Recruitment in the Microcirculation: the Rolling Paradigm Revisited
Authors: Kubes Paul , Kerfoot Steven M.
Published: December 2017

Intravital microscopy has done much to elucidate the cascade of events involved in the recruitment of leukocytes to sites of inflammation. Here we review the physiological relevance of leukocyte rolling and some of the important subtleties of this process, highlighting limitations in our knowledge and directions for future investigation.
Molecular Structure of Tight Junctions and Their Role in Epithelial Transport
Authors: Anderson James Melvin
Published: December 2017

Tight junctions create a paracellular barrier with physiological properties that differ among epithelia. Among these differences are electrical resistance and discrimination for solute size and charge. Emerging evidence suggests that a large family of transmembrane proteins called the claudins create these variable properties.
The Glutamine/Glutamate Couplet and Cellular Function
Authors: Welbourne Tomas , Routh Robert , Yudkoff Marc , Nissim Itzhak
Published: December 2017

All cells require glutamine as a nitrogen donor as well as an energy source for cell-specific functions. Understanding how glutamine utilization is metered to these demands is fundamental to basic cell processes as well as to therapeutic manipulation of regulatory mechanisms. The regulatory role of the glutamine/glutamate couplet in cellular function is illustrated for acid-base homeostasis and for production of the extracellular matrix.
Antibody-Based Targeting of Angiogenesis
Authors: Halin Cornelia , Zardi Luciano , Neri Dario
Published: December 2017

The selective targeting of neovasculature opens new avenues for the diagnosis and therapy of angiogenesis-related diseases such as cancer, blinding ocular disorders, and rheumatoid arthritis. Here we review recent advances in the identification of markers of angiogenesis as well as in the isolation and use of antibodies (and their derivatives) for the in vivo targeting of both tumoral and nontumoral neovasculature.
Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa
Authors: Dantzer Robert
Published: December 2017

Because of the compartmentalization of disciplines that shaped the academic landscape of biology and biomedical sciences in the past, physiological systems have long been studied in isolation from each other. This has particularly been the case for the immune system. As a consequence of its ties with pathology and microbiology, immunology as a discipline has largely grown independently of physiology. Accordingly, it has taken a long time for immunologists to accept the concept that the immune system is not self-regulated but functions in close association with the nervous system. These associations are present at different levels of organization. At the local level, there is clear evidence for the production and use of immune factors by the central nervous system and for the production and use of neuroendocrine mediators by the immune system. Short-range interactions between immune cells and peripheral nerve endings innervating immune organs allow the immune system to recruit local neuronal elements for fine tuning of the immune response. Reciprocally, immune cells and mediators play a regulatory role in the nervous system and participate in the elimination and plasticity of synapses during development as well as in synaptic plasticity at adulthood. At the whole organism level, long-range interactions between immune cells and the central nervous system allow the immune system to engage the rest of the body in the fight against infection from pathogenic microorganisms and permit the nervous system to regulate immune functioning. Alterations in communication pathways between the immune system and the nervous system can account for many pathological conditions that were initially attributed to strict organ dysfunction. This applies in particular to psychiatric disorders and several immune-mediated diseases. This review will show how our understanding of this balance between long-range and short-range interactions between the immune system and the central nervous system has evolved over time, since the first demonstrations of immune influences on brain functions. The necessary complementarity of these two modes of communication will then be discussed. Finally, a few examples will illustrate how dysfunction in these communication pathways results in what was formerly considered in psychiatry and immunology to be strict organ pathologies.
Life Span of Red Blood Cell
Authors: Berlin N. I. , Waldmann T. A. , Weissman S. M.
Published: December 2017

N. I. Berlin, T. A. Waldmann, and S. M. Weissman, “Life Span of Red Blood Cell”

Page 588, line 23, volume 39, should read: (see pdf)

Page 594, line 3, volume 39, should read: (see pdf)
Applications of Hodgkin-Huxley Equations to Excitable Tissue
Authors: Noble Denis
Published: December 2017

Denis Noble, “Applications of Hodgkin-Huxley Equations to Excitable Tissue,” p. 4, eq. 6a, should read:

See PDF for Equation
Control of the ductus arteriosus
Authors: Heymann M. A. , Rudolph A. M.
Published: December 2017

In the fetus the major function of the ductus arteriosus is to divert flow away from the lungs toward the placenta, therby avoiding unnecessary circulation through the lungs and reducing the work load of the heart. Constriction of the ductus arteriosus is produced by several mechanisms that may interact with one another in producing normal postnatal closure of the ductus arteriosus. The major mechanism is the constrictor effect of an increased O2 environment. This may directly affect the ductus arteriosus muscle or may work through the release of an intermediary substance. Other vasoactive substance circulating in the blood after birth may also play some role in constriction of the ductus arteriosus. There are major species differences in the degree and type of response to the various stimuli and the exact mechanisms ultimately responsible for closure are not yet fully understood.
Carnitine--metabolism and functions
Authors: Bremer J.
Published: December 2017

Carnitine was detected at the beginning of this century, but it was nearly forgotten among biochemists until its importance in fatty acid metabolism was established 50 years later. In the last 30 years, interest in the metabolism and functions of carnitine has steadily increased. Carnitine is synthesized in most eucaryotic organisms, although a few insects (and most likely some newborn animals) require it as a nutritional factor (vitamin BT). Carnitine biosynthesis is initiated by methylation of lysine. The trimethyllysine formed is subsequently converted to butyrobetaine in all tissues; the butyrobetaine is finally hydroxylated to carnitine in the liver and, in some animals, in the kidneys (see Fig. 1). It is released from these tissues and is then actively taken up by all other tissues. The turnover of carnitine in the body is slow, and the regulation of its synthesis is still incompletely understood. Microorganisms (e.g., in the intestine) can metabolize carnitine to trimethylamine, dehydrocarnitine (beta-keto-gamma-trimethylaminobutyric acid), betaine, and possibly to trimethylaminoacetone. In some insects carnitine can be converted to methylcholine, presumably with trimethylaminoacetone as an intermediate (see Fig. 3). In mammals the unphysiological isomer (+) carnitine is converted to trimethylaminoacetone. The natural isomer (-)carnitine is excreted unchanged in the urine, and it is still uncertain if it is degraded in mammalian tissues at all (Fig. 2). The only firmly established function of carnitine is its function as a carrier of activated fatty acids and activated acetate across the inner mitochondrial membrane. Two acyl-CoA:carnitine acyltransferases with overlapping chain-length specificities have been isolated: one acetyltransferase taking part in the transport of acetyl and short-chain acyl groups and one palmitoyltransferase taking part in the transport of long-chain acyl groups. An additional octanoyltransferase has been isolated from liver peroxisomes. Although a carnitine translocase that allows carnitine and acylcarnitine to penetrate the inner mitochondrial membrane has been deduced from functional studies (see Fig. 5), this translocase has not been isolated as a protein separate from the acyltransferases. Carnitine acetyltransferase and carnitine octanoyltransferase are also found in the peroxisomes. In these organelles the enzymes may be important in the transfer of acyl groups, which are produced by the peroxisomal beta-oxidation enzymes, to the mitochondria for oxidation in the citric acid cycle. The carnitine-dependent transport of activated fatty acids across the mitochondrial membrane is a regulated process. Malonyl-CoA inh
Differentiation of mammalian embryonic gonad
Authors: Byskov A. G.
Published: December 2017

Formation and differentiation of a gonad depend on finely controlled interactions between germ cells and various types of somatic cells. These interactions already begin when the germ cells start migrating toward the gonadal ridge. Reaching the presumptive gonadal area on the mesonephros, the germ cells join with the mesonephric-derived cells. These mesonephric cells are probably the precursors of the steroid-producing cells. A crucial event for gonadal function is the enclosure of germ cells and somatic cells in specific germ cell compartments. Survival and differentiation of the germ cells depend on this separation. Differentiation of the steroid-producing cells depends in turn on remaining outside the cell compartments. The mechanisms directing the gonad to develop into a testis or an ovary are still obscure, but specific gene products from the sex chromosomes probably play a basic role in gonadal sex differentiation.
Neutrophil kinetics and lung injury
Authors: Hogg J. C.
Published: December 2017

The fact that the lung stores a large proportion of the marginated pool of neutrophils is a result of the anatomy of the pulmonary microcirculation. This capillary bed is made up of a network of a very large number of segments, many of which have smaller diameters than the neutrophils. Both neutrophils and erythrocytes must deform to pass through the capillary bed, but as the neutrophils are larger and less deformable, they pass through the segments more slowly. The slower movement of neutrophils through the pulmonary capillaries produces little obstruction to erythrocyte flow because the very large number of segments allows the erythrocytes to stream around those that are filled with neutrophils. The size of the marginated pool of neutrophils in the lung depends on the balance between forces that propel the neutrophils through the capillary segments and those that tend to retard them. Activation of the PMN both decreases their deformability and increases their adherence to endothelium, which results in increased numbers of neutrophils in the lung and a reduction in the number circulating in the blood. There is growing evidence that the adherence of the neutrophil to the endothelial cell is mediated by the CD omega 18 on the surface of the neutrophil. The absence of these proteins leads to lack of neutrophil adherence and migration, whereas factors that enhance adherence lead to increased expression of these glycoproteins. The fact that activated neutrophils can also damage normal tissue has led to several attractive hypotheses concerning the pathogenesis of lung diseases such as emphysema and the ARDS. Further elucidation of factors that cause cells to marginate in the pulmonary circulation and a more complete understanding of the factors that control their adherence to endothelium, migration into the interstitial and airspace, and phagocytic function will undoubtedly lead to a better understanding of both the physiology and pathology of the lung.
Apolipoprotein genetic variation and human disease
Authors: Breslow J. L.
Published: December 2017

Atherosclerosis is the major public health problem in much of the world today. The information summarized in this review, based on the recognized apolipoprotein structural variants appreciated at both the protein and gene levels, indicates that apolipoprotein genetic variation plays a major role in determining human genetic susceptibility to this disease. With the use of cloned apolipoprotein genes, it should, in the near future, be possible to determine how their expression is regulated; this should provide insight into other classes of mutations of a regulatory nature that might have clinical significance. In addition, the many association and linkage studies currently being undertaken will provide the rationale for cloning defective alleles and determining specific causative mutations. Both structural and regulatory mutations can then be described either with restriction enzymes and Southern blotting or by direct oligonucleotide hybridization techniques in the general population. This will allow the identification of presymptomatic atherosclerosis-susceptible individuals who would be targets for primary preventative therapy.
Control and function of sebaceous glands
Authors: Thody A. J. , Shuster S.
Published: December 2017

This review describes the various types of sebaceous glands, their locations, and where possible their different functions. All sebaceous glands are similar in structure and secrete sebum by a holocrine process. However, the nature of this secretion and the regulation of the secretory process seem to differ among the various types of glands. Methods for measuring sebum secretion and assessing sebaceous gland activity are also described. The area of major interest during the last 20 years has undoubtedly been the mechanisms that control sebaceous gland function. Most studies have focused on the endocrine control and in particular on the role of androgens and pituitary hormones, although evidence suggests that nonendocrine factors may also be important. However, many questions remain and during the next few years attention will certainly be given to the role of retinoids and their mode of action in the treatment of acne.
Intrinsic regulation of apical sodium entry in epithelia
Authors: Turnheim K.
Published: December 2017

In the past 30 years the basic features of Na+ absorption by epithelia have been unraveled and generally accepted cell models have been established. However, these cell models of transepithelial Na+ transport represent, for the most part, a static view of cell function, i.e., all transport parameters are assumed to be in a steady state. Today the focus is on the dynamic properties of epithelia, the non-steady-state condition, and the adaptation to environmental or transport changes. This review deals with mechanisms intrinsic to the epithelium that regulate apical membrane Na+ permeability in response to changes in transport load and ambient conditions. Together with parallel autoregulatory events concerning the basolateral K+ conductance, the described mechanisms controlling apical membrane Na+ permeability serve to maintain the intracellular ionic composition within the limits that are compatible with cell function and survival. Extraepithelial factors that influence epithelial Na+ transport such as mineralocorticoids and glucocorticoids, ADH, catecholamines, and other neurotransmitters are discussed elsewhere. Apical membrane Na+ permeability appears to be determined by several intrinsic or autoregulatory mechanisms. The PmNa of epithelia with channel-mediated apical Na+ entry is downregulated by increases in the Na+ concentration of the apical bathing solution (self-inhibition) and by procedures that inhibit basolateral Na+ extrusion (feedback inhibition). The underlying mechanisms of both regulatory systems are unclear. With the use of current-noise (fluctuation) analysis, on the one hand, and single-channel recordings, on the other hand, conflicting results were obtained concerning the saturability of single-channel conductance with increasing external Na+ concentrations. Results from Na(+)-uptake studies in apical membrane vesicles from amiloride-sensitive epithelia render it unlikely that cell Na+ itself is the mediator of feedback inhibition. Both self-inhibition and feedback inhibition of PmNa are prevented by titrating superficial sulfhydryl groups in the apical membrane. Elevations of cell Ca2+ decrease apical Na+ entry, possibly via an indirect mechanism involving protein kinase C. The PmNa is markedly dependent on cell metabolism and pHc; inhibition of ATP supply and lowering cell pH reduce PmNa. Additionally, PmNa may be altered by exocytotic expansion and endocytotic retrieval of the apical membrane area or by insertion of channel proteins into the apical membrane without increasing the apical membrane area. The diversity of regulatory systems may insure the high degree of flexibility and plasticity of epithelia in their response to environmental changes.
Cellular calcium transport in renal epithelia: measurement, mechanisms, and regulation
Authors: Friedman P. A. , Gesek F. A.
Published: December 2017

The kidneys play a vital role in mineral homeostasis. In this review, the handling of calcium and the methods currently applied to measuring its intracellular concentration are discussed. The bulk of calcium absorption proceeds in proximal tubules, with smaller fractions recovered by thick ascending limbs, distal convoluted tubules, and connecting tubules. Hormonally regulated transcellular calcium absorption is essentially limited to distal convoluted and connecting tubules. At physiological concentrations, parathyroid hormone, calcitonin, and vitamin D increase net calcium absorption. Calcium absorption by polarized epithelial cells is a two-step process wherein calcium enters the cell across apical plasma membranes and exits across basolateral membranes. Recent electrophysiological and pharmacological experiments demonstrate that apical entry is mediated by calcium channels, which are modestly calcium selective, sensitive to dihydropyridine-type calcium channel blockers, and exhibit a wide range of single-channel conductances. Cellular calcium efflux is mediated by Ca(2+)-ATPase and by Na+/Ca2+ exchange. Ca(2+)-ATPase activity is highest in segments that exhibit significant rates of active calcium absorption. Multiple plasma membrane Ca(2+)-ATPase isoforms have been found in the kidney. Several renal Na+/Ca2+ exchange isoforms have been identified, and their role in effecting calcium efflux is under investigation.
Pathophysiology of insulin resistance in human disease
Authors: Reaven G. M.
Published: December 2017

The ability of insulin to stimulate glucose uptake varies widely from person to person, and these differences, as well as how the individual attempts to compensate for them, are of fundamental importance in the development and clinical course of what are often designated as diseases of Western civilization. Evidence is presented that non-insulin-dependent diabetes mellitus (NIDDM) results from a failure on the part of pancreatic beta-cells to compensate adequately for the defect in insulin action in insulin-resistant individuals. In addition, a coherent formulation of the physiological changes that lead from the defect in cellular insulin action to the loss in glucose homeostasis is presented. However, the ability to maintain the degree of compensatory hyperinsulinemia necessary to prevent loss of glucose tolerance in insulin-resistant individuals does not represent an unqualified homeostatic victory. In contrast, evidence is presented supporting the view that the combination of insulin resistance and compensatory hyperinsulinemia predisposes to the development of a cluster of abnormalities, including some degree of glucose intolerance, an increase in plasma triglyceride and a decrease in high-density lipoprotein cholesterol concentrations, high blood pressure, hyperuricemia, smaller denser low-density lipoprotein particles, and higher circulating levels of plaminogen activator inhibitor 1. The cluster of changes associated with insulin resistance has been said to comprise syndrome X, and all of the manifestations of syndrome X have been shown to increase risk of coronary heart disease. Thus it is concluded that insulin resistance and its associated abnormalities are of utmost importance in the pathogenesis of NIDDM, hypertension, and coronary heart disease.
The asialoglycoprotein receptor: relationships between structure, function, and expression
Authors: Stockert R. J.
Published: December 2017

Transport of macromolecules into the cell by receptor-mediated endocytosis follows a complex series of intracellular transfers, passing through distinct environments. The asialoglycoprotein receptor is a prototype of the class of receptors that constitutively enters cells via coated pits and delivers ligand to these intracellular compartments. In addition to being a model of receptor-mediated endocytosis, the presence of the receptor on hepatocytes provides a membrane-bound active site for cell-to-cell interactions, has made possible the selective targeting of chemotherapeutic agents and foreign genes, and has also been implicated as a site mediating hepatitis B virus uptake. Regulated expression of receptor subunits and their intracellular trafficking during biosynthesis and endocytosis has provided insights into the relationship of receptor structure to its overall function. As a marker of hepatocellular differentiation, its study has uncovered a unique response to intracellular guanosine 3',5'-cyclic monophosphate and translational regulation of the receptor. In this review, an overview of these diverse findings is provided in an attempt to relate the various aspects of structure and function as they impact on receptor expression.
Nonsynaptic modulation of neuronal activity in the brain: electric currents and extracellular ions
Authors: Jefferys J. G.
Published: December 2017

Nonsynaptic interactions between neurons have been eclipsed by our increasingly detailed understanding of chemical synapses, but they do play significant roles in the nervous system. This review considers four classes of nonsynaptic interaction, mainly in mammalian brain. 1) Electrotonic (and chemical) coupling through gap junctions has effects during development and under some, often pathological, conditions in the mature brain. 2) Ephaptic transmission is mediated by electrical coupling between specific neuronal elements in the absence of specialized contacts, notably in the cerebellum, and in axon tracts affected by demyelination. 3) Field effect interactions are mediated by large extracellular currents and potential fields generated by the hippocampus and other cortical structures. Both endogenous and applied electric fields alter neuronal excitability at field strengths over a few millivolts per millimeter. Weaker fields have more subtle effects, for instance, on axonal growth during development and repair and, more controversially, in behavioral responses to environmental fields. 4) There are fluctuations in extracellular ions such as K+, which are released during neuronal activity and which alter neuronal excitability. Field effects and ion fluctuations probably have modest effects during physiological activity but have a significant impact on epileptic seizures, and can sustain them in the absence of synaptic transmission.
Cyclic nucleotide phosphodiesterases: functional implications of multiple isoforms
Authors: Beavo J. A.
Published: December 2017

In the last few years there has been a veritable explosion of knowledge about cyclic nucleotide phosphodiesterases. In particular, the accumulating data showing that there are a large number of different phosphodiesterase isozymes have triggered an equally large increase in interest about these enzymes. At least seven different gene families of cyclic nucleotide phosphodiesterase are currently known to exist in mammalian tissues. Most families contain several distinct genes, and many of these genes are expressed in different tissues as functionally unique alternative splice variants. This article reviews many of the more important aspects about the structure, cellular localization, and regulation of each family of phosphodiesterases. Particular emphasis is placed on new information obtained in the last few years about how differential expression and regulation of individual phosphodiesterase isozymes relate to their function(s) in the body. A substantial discussion of the currently accepted nomenclature is also included. Finally, a brief discussion is included about how the differences among distinct phosphodiesterase isozymes are beginning to be used as the basis for developing therapeutic agents.
Dynamics of nerve-muscle interaction in developing and mature neuromuscular junctions
Authors: Grinnell A. D.
Published: December 2017

Neuromuscular connections have long served as models of synaptic structure and function. They also provide illuminating insights into the dynamic cell-cell interactions governing synaptogenesis, neuromuscular differentiation, and the maintenance of effective function. This paper reviews recent advances in our understanding of the regulatory and inductive interactions involved in motor axon pathfinding, target recognition, bidirectional control of gene expression during synapse formation, motoneuron cell death, terminal rearrangement, and the ongoing remodeling of synaptic number, structure, and function to adjust to growth and changes in use.
Protein trafficking and polarity in kidney epithelium: from cell biology to physiology
Authors: Brown D. , Stow J. L.
Published: December 2017

The transepithelial movement of fluids, electrolytes, and larger molecules is achieved by the activity of a host of specialized transporting proteins, including enzymes, receptors, and channels, that are located on either the apical, basal, or lateral plasma membrane domains of epithelial cells. In the kidney as well as in all other organs, this remarkable polarity of epithelial cells depends on the selective insertion of newly synthesized and recycling proteins and lipids into distinct plasma membrane domains and on the maintenance and modulation of these specialized domains once they are established during epithelial development. This review addresses the mechanisms by which epithelial cells control the movement of membrane components within the cell to ensure that they are delivered to the correct target membrane. Among the topics discussed are targeting signals within membrane proteins, the role of the cytoskeleton and the tight junctional barrier in cell polarity, and the requirement for accessory proteins in the targeting process, including GTP-binding proteins, and proteins that are involved in vesicle docking and fusion events. The final part of the review is devoted uniquely to the polarized targeting of functionally defined proteins in various kidney cell types. In concluding, examples of how a breakdown in these trafficking pathways may be related to some disease states are presented.
Structure and functional mechanism of porins
Authors: Jap B. K. , Walian P. J.
Published: December 2017

Cellular organisms such as gram-negative bacteria are enclosed by a dual lipid bilayer system. The outer membranes of the dual bilayer envelopes predominantly contain large numbers of water-filled transmembrane protein channels known as porins. The recent availability of the molecular structures of several bacterial porins has provided the opportunity for comparing the results of a wide range of functional studies with the atomic level structural details of these membrane channels. Taken together, the structure and function data present the most comprehensive set of boundary conditions available for the evaluation of theory and models predicting the characteristics of solute transport through membrane protein channels. In this paper, we review the high-resolution structure data from the bacterial porins, as well as recent theoretical studies, in the context of biophysical and biochemical observations and discuss the molecular mechanisms responsible for the transport of solutes through porin channels. Particular emphasis has been placed on the features and roles of common structural elements, channel sterics and electrostatics, and voltage-dependent gating. A model for water-coordinated transport, providing a qualitative view of the porin transport mechanism, is also described.
Developmental models of brain dysfunctions induced by targeted cellular ablations with methylazoxymethanol
Authors: Cattabeni F. , Di Luca M.
Published: December 2017

Abnormal brain development represents one of the major causes of neurological disorders in humans, and determining the factors responsible for generating specific brain malformations represents a formidable task for developmental neurobiology. The knowledge of the precise neurogenetic time table and the use of toxins, like methylazoxymethanol, able to interfere with neuroepithelial cells entering their last mitotic cycle, have allowed for targeted neuronal ablations in specific brain areas of the central nervous system (CNS) when administered at different gestational or postnatal days in various animal species. Of particular relevance are the studies in which ablations of neuronal populations of cortex, hippocampus, and cerebellum have been made. The results obtained show that these early ablations induce a number of neuroanatomic, neurochemical, and electrophysiological changes that give us the possibility to unravel the biochemical strategies utilized by surviving neurons to adapt to the perturbated environment. Most striking are the findings that target deprivation does not affect the survival of afferent neurons in the CNS (except for neurons of the lateral geniculate nucleus), in sharp contrast to the notion of target dependence for peripheral nervous system neurons. Animals showing selective ablations in the Ammon's horn of the hippocampus allow us to understand the complex biochemical pathways leading to changes in activity-dependent synaptic plasticity, and the data underscore the fundamental role of diverse Ca(2+)-dependent protein kinases, and their substrates, in modulating pre- and postsynaptic events during induction and maintenance of long-term potentiation (LTP). Because LTP represents a useful model to study molecular substrates of learning and memory, this animal model might be of relevance in understanding cognitive brain dysfunctions.
Immunomodulatory functions of surfactant
Authors: Wright J. R.
Published: December 2017

The possibility that the lipoprotein complex of lung surfactant functions in pulmonary host defense as well as lowering surface tension at the air-liquid interface has been the subject of renewed interest in light of the finding that surfactant proteins A and D (SP-A and SP-D) are members of a family of proteins known as collectins. The collectins, so named because they have in common an NH2-terminal collagen-like domain and a COOH-terminal lectin (carbohydrate binding) domain, are found in both lung and serum and participate in "innate" immunity, acting before induction of an antibody-mediated response. In vitro, many of the collectins stimulate phagocytosis, chemotaxis, and production of reactive oxygen and regulate cytokine release by immune cells. It has been known for several years that surfactant lipids suppress a variety of immune cell functions, most notably lymphocyte proliferation, which, conversely, is augmented by SP-A. Thus surfactant lipids and proteins may be counterregulatory, and changes in lipid-to-protein ratios may be important in regulating the immune status of the lung. That these ratios change in disease states is clear, but it is not known whether the alterations are a cause or an effect. Important future studies with mice in which the SP-A and SP-D genes have been ablated will help clarify the role of surfactant in immune function.
Using Knockout and Transgenic Mice to Study Neurophysiology and Behavior
Authors: PICCIOTTO MARINA R. , WICKMAN KEVIN
Published: December 2017

Picciotto, Marina R., and Kevin Wickman. Using Knockout and Transgenic Mice to Study Neurophysiology and Behavior. Physiol. Rev. 78: 1131–1163, 1998. — Reverse genetics, in which detailed knowledge of a gene of interest permits in vivo modification of its expression or function, provides a powerful method for examining the physiological relevance of any protein. Transgenic and knockout mouse models are particularly useful for studies of complex neurobiological problems. The primary aims of this review are to familiarize the nonspecialist with the techniques and limitations of mouse mutagenesis, to describe new technologies that may overcome these limitations, and to illustrate, using representative examples from the literature, some of the ways in which genetically altered mice have been used to analyze central nervous system function. The goal is to provide the information necessary to evaluate critically studies in which mutant mice have been used to study neurobiological problems.
Epithelial Transport in Polycystic Kidney Disease
Authors: SULLIVAN LAWRENCE P. , WALLACE DARREN P. , GRANTHAM JARED J.
Published: December 2017

Sullivan, Lawrence P., Darren P. Wallace, and Jared J. Grantham. Epithelial Transport in Polycystic Kidney Disease. Physiol. Rev. 78: 1165–1191, 1998. — In autosomal dominant polycystic kidney disease (ADPKD), the genetic defect results in the slow growth of a multitude of epithelial cysts within the renal parenchyma. Cysts originate within the glomeruli and all tubular structures, and their growth is the result of proliferation of incompletely differentiated epithelial cells and the accumulation of fluid within the cysts. The majority of cysts disconnect from tubular structures as they grow but still accumulate fluid within the lumen. The fluid accumulation is the result of secretion of fluid driven by active transepithelial Cl−secretion. Proliferation of the cells and fluid secretion are activated by agonists of the cAMP signaling pathway. The transport mechanisms involved include the cystic fibrosis transmembrane conductance regulator (CFTR) present in the apical membrane of the cystic cells and a bumetanide-sensitive transporter located in the basolateral membrane. A lipid factor, called cyst activating factor, has been found in the cystic fluid. Cyst activating factor stimulates cAMP production, proliferation, and fluid secretion by cultured renal epithelial cells and also is a chemotactic agent. Cysts also appear in the intrahepatic biliary tree in ADPKD. Normal ductal cells secrete Cl−and HCO−3. The cystic ductal cell also secretes Cl−, but HCO−3secretion is diminished, probably as the result of a lower population of Cl−/HCO−3exchangers in the apical membrane as compared with the normal cells. Some segments of the normal renal tubule are also capable of utilizing CFTR to secrete Cl−, particularly the inner medullary collecting duct. The ability of Madin-Darby canine kidney cells and normal human kidney cortex cells to form cysts in culture and to secrete fluid and the functional similarities between these incompletely differentiated, proliferative cells and developing cells in the intestinal crypt and in the fetal lung have led us to suggest that Cl−and fluid secretion may be a common property of at least some renal epithelial cells in an intermediate stage of development. The genetic defect in ADPKD may not directly affect membrane transport mechanisms but rather may arrest the development of certain renal epithelial cells in an incompletely differentiated, proliferative stage.
Phospholamban: Protein Structure, Mechanism of Action, and Role in Cardiac Function
Authors: SIMMERMAN HEATHER K. B. , JONES LARRY R.
Published: December 2017

Simmerman, Heather K. B., and Larry R. Jones. Phospholamban: Protein Structure, Mechanism of Action, and Role in Cardiac Function. Physiol. Rev. 78: 921–947, 1998. — A comprehensive discussion is presented of advances in understanding the structure and function of phospholamban (PLB), the principal regulator of the Ca2+-ATPase of cardiac sarcoplasmic reticulum. Extensive historical studies are reviewed to provide perspective on recent developments. Phospholamban gene structure, expression, and regulation are presented in addition to in vitro and in vivo studies of PLB protein structure and activity. Applications of breakthrough experimental technologies in identifying PLB structure-function relationships and in defining its interaction with the Ca2+-ATPase are also highlighted. The current leading viewpoint of PLB's mechanism of action emerges from a critical examination of alternative hypotheses and the most recent experimental evidence. The potential physiological relevance of PLB function in human heart failure is also covered. The interest in PLB across diverse biochemical disciplines portends its continued intense scrutiny and its potential exploitation as a therapeutic target.
Pharmacology of CFTR Chloride Channel Activity
Authors: SCHULTZ B. D. , SINGH A. K. , DEVOR D. C. , BRIDGES R. J.
Published: December 2017

Schultz, B. D., A. K. Singh, D. C. Devor, and R. J. Bridges. Pharmacology of CFTR Chloride Channel Activity. Physiol. Rev. 79, Suppl.: S109–S144, 1999. — The pharmacology of cystic fibrosis transmembrane conductance regulator (CFTR) is at an early stage of development. Here we attempt to review the status of those compounds that modulate the Cl−channel activity of CFTR. Three classes of compounds, the sulfonylureas, the disulfonic stilbenes, and the arylaminobenzoates, have been shown to directly interact with CFTR to cause channel blockade. Kinetic analysis has revealed the sulfonylureas and arylaminobenzoates interact with the open state of CFTR to cause blockade. Suggestive evidence indicates the disulfonic stilbenes act by a similar mechanism but only from the intracellular side of CFTR. Site-directed mutagenesis studies indicate the involvement of specific amino acid residues in the proposed transmembrane segment 6 for disulfonic stilbene blockade and segments 6 and 12 for arylaminobenzoate blockade. Unfortunately, these compounds (sulfonylureas, disulfonic stilbenes, arylaminobenzoate) also act at a number of other cellular sites that can indirectly alter the activity of CFTR or the transepithelial secretion of Cl−. The nonspecificity of these compounds has complicated the interpretation of results from cellular-based experiments. Compounds that increase the activity of CFTR include the alkylxanthines, phosphodiesterase inhibitors, phosphatase inhibitors, isoflavones and flavones, benzimidazolones, and psoralens. Channel activation can arise from the stimulation of the cAMP signal transduction cascade, the inhibition of inactivating enzymes (phosphodiesterases, phosphatases), as well as the direct binding to CFTR. However, in contrast to the compounds that block CFTR, a detailed understanding of how the above compounds increase the activity of CFTR has not yet emerged.
Role of CFTR in Airway Disease
Authors: PILEWSKI JOSEPH M. , FRIZZELL RAYMOND A.
Published: December 2017

Pilewski, Joseph M., and Raymond A. Frizzell. Role of CFTR in Airway Disease. Physiol. Rev. 79, Suppl.: S215–S255, 1999. — Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), which accounts for the cAMP-regulated chloride conductance of airway epithelial cells. Lung disease is the chief cause of morbidity and mortality in CF patients. This review focuses on mechanisms whereby the deletion or impairment of CFTR chloride channel function produces lung disease. It examines the major themes of the channel hypothesis of CF, which involve impaired regulation of airway surface fluid volume or composition. Available evidence indicates that the effect of CFTR deletion alters physiological functions of both surface and submucosal gland epithelia. At the airway surface, deletion of CFTR causes hyperabsorption of sodium chloride and a reduction in the periciliary salt and water content, which impairs mucociliary clearance. In submucosal glands, loss of CFTR-mediated salt and water secretion compromises the clearance of mucins and a variety of defense substances onto the airway surface. Impaired mucociliary clearance, together with CFTR-related changes in the airway surface microenvironment, leads to a progressive cycle of infection, inflammation, and declining lung function. Here, we provide the details of this pathophysiological cascade in the hope that its understanding will promote the development of new therapies for CF.
Neuroendocrine Control of Growth Hormone Secretion
Authors: Müller Eugenio E. , Locatelli Vittorio , Cocchi Daniela
Published: December 2017

The secretion of growth hormone (GH) is regulated through a complex neuroendocrine control system, especially by the functional interplay of two hypothalamic hypophysiotropic hormones, GH-releasing hormone (GHRH) and somatostatin (SS), exerting stimulatory and inhibitory influences, respectively, on the somatotrope. The two hypothalamic neurohormones are subject to modulation by a host of neurotransmitters, especially the noradrenergic and cholinergic ones and other hypothalamic neuropeptides, and are the final mediators of metabolic, endocrine, neural, and immune influences for the secretion of GH. Since the identification of the GHRH peptide, recombinant DNA procedures have been used to characterize the corresponding cDNA and to clone GHRH receptor isoforms in rodent and human pituitaries. Parallel to research into the effects of SS and its analogs on endocrine and exocrine secretions, investigations into their mechanism of action have led to the discovery of five separate SS receptor genes encoding a family of G protein-coupled SS receptors, which are widely expressed in the pituitary, brain, and the periphery, and to the synthesis of analogs with subtype specificity. Better understanding of the function of GHRH, SS, and their receptors and, hence, of neural regulation of GH secretion in health and disease has been achieved with the discovery of a new class of fairly specific, orally active, small peptides and their congeners, the GH-releasing peptides, acting on specific, ubiquitous seven-transmembrane domain receptors, whose natural ligands are not yet known.
Apocalmodulin
Authors: Jurado Luis A. , Chockalingam Priya Sethu , Jarrett Harry W.
Published: December 2017

Intracellular Ca2+is normally maintained at submicromolar levels but increases during many forms of cellular stimulation. This increased Ca2+binds to receptor proteins such as calmodulin (CaM) and alters the cell’s metabolism and physiology. Calcium-CaM binds to target proteins and alters their function in such a way as to transduce the Ca2+signal. Calcium-free or apocalmodulin (ApoCaM) binds to other proteins and has other specific effects. Apocalmodulin has roles in the cell that apparently do not require the ability to bind Ca2+at all, and these roles appear to be essential for life. Apocalmodulin differs from Ca2+-CaM in its tertiary structure. It binds target proteins differently, utilizing different binding motifs such as the IQ motif and noncontiguous binding sites. Other kinds of binding potentially await discovery. The ApoCaM-binding proteins are a diverse group of at least 15 proteins including enzymes, actin-binding proteins, as well as cytoskeletal and other membrane proteins, including receptors and ion channels. Much of the cellular CaM is bound in a Ca2+-independent manner to membrane structures within the cell, and the proportion bound changes with cell growth and density, suggesting it may be a storage form. Apocalmodulin remains tightly bound to other proteins as subunits and probably hastens the response of these proteins to Ca2+. The overall picture that emerges is that CaM cycles between its Ca2+-bound and Ca2+-free states and in each state binds to different proteins and performs essential functions. Although much of the research focus has been on the roles of Ca2+-CaM, the roles of ApoCaM are equally vital but less well understood.