bluuebunny/crossref_metadata_2025 huggingface dataset:
Replicative senescence of human fibroblast-like cells in culture
Authors: Cristofalo V. J. , Pignolo R. J.
Published: December 2017

The life history of fibroblast and fibroblast-like cells includes an initial stage of outgrowth and establishment in culture; a period of vigorous proliferation which has a variable length, depending on the tissue of origin, age of the donor, etc.; a period of declining proliferative vigor which includes substantial cell death; and finally, the emergence of an (apparently) long-lived population which is unable to proliferate in response to growth factors. During the phase of declining proliferative vigor, the cells acquire characteristics, some of which are similar to the characteristics of cells in older individuals. Eventually the culture completely loses proliferative capacity. A comparable life history has been described for glial cells, keratinocytes, vascular smooth muscle cells, endothelial cells, and lymphocytes which suggests that this life history is characteristic of those cell types that, in vivo, retain the capacity for proliferation throughout the life span. Numerous studies have shown a correlation between the age of the tissue donor and the replicative life span of the cells in culture. In addition, for a small sample of species, there is a direct correlation between fibroblast replicative life span in vitro and maximum life span potential of the species. The period in the life history that is usually referred to as the "senescent phase" is probably more complicated than was originally thought, since studies with life span modulators suggest that there is a "conditionally" senescent state from which cells can be rescued for one or more additional rounds of DNA synthesis. Finally, the cells enter an "obligatory" arrested state in which only SV40 infection can reverse the block to DNA synthesis but not the block to mitosis. The modern era of aging research in tissue culture is just over 30 years old. The inception of the field really began with the recognition by Hayflick and Moorhead (109) that the phenomenon of senescence in vitro paralleled, in some of its characteristics, cell aging in vivo and thus provided a model that could be used to study the cellular mechanisms underlying senescence in controlled environmental conditions. The research in this area began with a detailed characterization and comparison of young versus senescent cell morphology and physiology. These studies provided the basis for a wide variety of subsequent studies that addressed possible mechanisms underlying cell senescence. These included studies on DNA repair, protein synthetic errors, chromatin structure and function, and mechanisms for modulating replicative life span.(ABSTRACT TRUNCATED AT 400 WORDS)
Flow-mediated endothelial mechanotransduction
Authors: Davies P. F.
Published: December 2017

Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major regulation of the blood vessel responses occurs by the action of hemodynamic shear stresses on the endothelium. The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.
Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation
Authors: Edwards F. A.
Published: December 2017

Detailed knowledge of the anatomy of central synapses is essential to the interpretation of the vast quantity of electrophysiological findings that have been published in recent years. When their function is considered, it is not surprising that, in both anatomy and electrophysiology, fast central synapses show important differences to the neuromuscular junction. This review concentrates on the detailed anatomy of the common excitatory synapses that impinge on dendritic spines, but also refers to other glutamatergic and GABAergic synapses. This information is brought together with present knowledge of the electrophysiology of fast neurotransmission in the brain. Various types of evidence are outlined, explaining why it is now widely accepted that release of transmitter from a single vesicle virtually saturates the small number of receptors available on the postsynaptic membrane of central synapses. Finally, the anatomic literature suggests that a particular type of spine synapse, which electron microscopy reveals to have a perforated active zone, may represent a synapse with high efficacy. This suggestion is shown to be completely compatible with the electrophysiological data, and a model is presented that shows that all the apparently conflicting data in the field of long-term potentiation could be compatible. This stresses the need for cooperative collaboration between laboratories that have apparently conflicting findings.
Modulation of cardiovascular control mechanisms and their interaction
Authors: Persson P. B.
Published: December 2017

It is generally held that the role of a specific control element can only be understood within its physiological environment. The reviewed studies make it clear that there is a potent interplay between locally produced substances such as adenosine, nitric oxide, prostaglandins, and various others all interacting with the central level of control. This can occur at central sites (e.g., nitric oxide in the brain) or in the periphery (e.g., neural influence on autoregulation). The interactions are more or less pronounced during specific physiological challenges. Furthermore, several of these interactions are altered under pathological circumstances, and in some cases, the interactions seem to maintain or even augment the severity of disease. When more than three parameters participate in an interaction, the resulting regulation may become extremely complex. If these parameters are nonlinearly coupled with each other, the only way to shed light onto the nature of control network is by treating it as a black box. With the use of spectral analysis or nonlinear methods, it is possible to disentangle the fundamental nature of the system in terms of the complexity and stability. Therefore, modern developments in cardiovascular physiology utilizing these techniques, some of which are derived from the "chaos theory," are reviewed.
Physiology and biochemistry of Drosophila learning mutants
Authors: Davis R. L.
Published: December 2017

Single gene mutants of Drosophila that are defective in learning/memory processes have increased substantially our understanding of the physiology, biochemistry, and anatomy underlying conditioned behaviors. Drosophila learning mutants can be separated into two general classes, those with structural defects in the brain and those without (conditioning mutants) any obvious brain alterations. From studies of brain structural mutants, two neuroanatomic areas have merged as important for normal conditioned behavior: the mushroom bodies and the central complex. Biochemical and molecular genetic studies of the conditioning mutants have implicated numerous types of molecules in learning, but the adenosine 3',5'-cyclic monophosphate (cAMP) second messenger pathway has emerged as especially important. Five different genes in this pathway, amnesiac (a product similar to adenylate cyclase activating peptides), dunce (cAMP phosophodiesterase), rutabaga (adenylyl cyclase), DCO (protein kinase A), and dCREB2 (cAMP-response element binding protein), have proven important for normal learning. The products of many of these learning mutants are enriched in mushroom bodies, which highlight the importance of mushroom bodies for normal learning and the cAMP second messenger cascade for the physiology of mushroom body cells in their role(s) underlying learning. Physiological studies of the mutants have demonstrated that plastic properties of synaptic transmission, including facilitation and posttetanic potentiation, are abnormal in the mutants. An appendix describing the currently used paradigms to test Drosophila behavior is included.
Molecular diversity of myofibrillar proteins: gene regulation and functional significance
Authors: Schiaffino S. , Reggiani C.
Published: December 2017

Myofibrillar proteins exist as multiple isoforms that derive from multigene (isogene) families. Additional isoforms, including products of tropomyosin, myosin light chain 1 fast, troponin T, titin, and nebulin genes, can be generated from the same gene through alternative splicing or use of alternative promoters. Myofibrillar protein isogenes are differentially expressed in various muscle types and fiber types but can be coexpressed within the same fiber. Isogenes are regulated by transcriptional and posttranscriptional mechanisms; however, specific regulatory sequences and transcriptional factors have not yet been identified. The pattern of isogene expression varies during muscle development in relation to the different origin of myogenic cells and primary/secondary fiber generations and is affected by neural and hormonal influences. The variable expression of myofibrillar protein isoforms is a major determinant of the contractile properties of skeletal muscle fibers. The diversity among isomyosins is related to the differences in the parameters of chemomechanical transduction as ATP hydrolysis rate and shortening velocity. Troponin and tropomyosin isoforms determine the variable sensitivity to calcium, whereas titin isoforms dictate the elastic properties of muscle fibers at rest. Both myosin and troponin isoforms contribute to the differences in the resistance to fatigue of muscle fibers.
Transcriptional control of osteoblast growth and differentiation
Authors: Stein G. S. , Lian J. B. , Stein J. L. , Van Wijnen A. J. , Montecino M.
Published: December 2017

Osteoblast differentiation is a multistep series of events modulated by an integrated cascade of gene expression that initially supports proliferation and the sequential expression of genes associated with the biosynthesis, organization, and mineralization of the bone extracellular matrix. Transcriptional control defines regulatory events operative both developmentally and for support of bone tissue-specific properties. This review focuses on components of transcriptional regulation that function in growth control during osteoblast proliferation and those that postproliferatively contribute to maturation of the bone phenotype. Emphasis is on transcription of the cell cycle-regulated histone gene and the bone-specific osteocalcin gene as paradigms for genes with promoter elements exhibiting responsiveness to a broad spectrum of physiological regulatory signals. Additionally, the potential contributions provided by the three-dimensional organization of the histone and osteocalcin gene promoters to integration of regulatory activities at multiple, independent, and overlapping regulatory domains are explored.
Taste reception
Authors: Lindemann B.
Published: December 2017

Recent research on cellular mechanisms of peripheral taste has defined transduction pathways involving membrane receptors, G proteins, second messengers, and ion channels. Receptors for organic tastants received much attention, because they provide the specificity of a response. Their future cloning will constitute a major advance. Taste transduction typically utilizes two or more pathways in parallel. For instance, sweet-sensitive taste cells of the rat appear to respond to sucrose with activation of adenylyl cyclase, followed by adenosine 3',5'-cyclic monophosphate (cAMP)-dependent membrane events and Ca2+ uptake. The same cells respond differently to some artificial sweeteners, i.e., with activation of phospholipase C (PLC) followed by inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ release from intracellular stores. Some bitter tastants block K+ channels or initiate the cascade receptor G1 protein, PLC, IP3, and Ca2+ release or the cascade receptor alpha-gustducin, phosphodiesterase (PDE), cAMP decrease, and opening of cAMP-blocked channels. Membrane-permeant bitter tastants may elicit a cellular response by interacting with G protein, PLC, or PDE of the above cascades. Salt taste is initiated by current flowing into the taste cell through cation channels located in the apical membrane, even though basolateral channels may also contribute (following salt diffusion through paracellular pathways). In rodents, the Na+-specific component of salt taste is typically mediated by apical amiloride-sensitive Na+ channels, but less specific and not amiloride-sensitive taste components exist in addition. Sour taste may in part be mediated by amiloride-sensitive Na+ channels conducting protons, but other mechanisms certainly contribute. Thus the transduction of taste cells generally comprises parallel pathways. Furthermore, the transduction pathways vary with the location of taste buds on the tongue and, of course, across species of animals. To identify these pathways, to understand how they are controlled and why they evolved to this complexity are major goals of present research.
Ryanodine receptor Ca2+ release channels: does diversity in form equal diversity in function?
Authors: Sutko J. L. , Airey J. A.
Published: December 2017

Complexities in calcium signaling in eukaryotic cells require diversity in the proteins involved in generating these signals. In this review, we consider the ryanodine receptor (RyR) family of intracellular calcium release channels. This includes species, tissue, and cellular distributions of the RyRs and mechanisms of activation, deactivation, and inactivation of RyR calcium release events. In addition, as first observed in nonmammalian vertebrate skeletal muscles, it is now clear that more than one RyR isoform is frequently coexpressed within many cell types. How multiple ryanodine receptor release channels are used to generate intracellular calcium transients is unknown. Therefore, a primary focus of this review is why more than one RyR is required for this purpose, particularly in a tissue, such as vertebrate fast-twitch skeletal muscles, where a relatively simple and straightforward change in calcium would appear to be required to elicit contraction. Finally, the roles of the RyR isoforms and the calcium release events they mediate in the development of embryonic skeletal muscle are considered.
Endocytosis
Authors: Mukherjee S. , Ghosh R. N. , Maxfield F. R.
Published: December 2017

Mammalian cells take up extracellular material by a variety of different mechanisms that are collectively termed endocytosis. Endocytic mechanisms serve many important cellular functions including the uptake of extracellular nutrients, regulation of cell-surface receptor expression, maintenance of cell polarity, and antigen presentation. Endocytic pathways are also utilized by viruses, toxins, and symbiotic microorganisms to gain entry into cells. One of the best-characterized endocytic mechanisms is receptor-mediated endocytosis via clathrin-coated pits. This type of endocytosis constitutes the major emphasis of this review, with a brief discussion of other endocytic mechanisms and their comparison with the receptor-mediated pathway. This review describes and evaluates critically current understanding of the mechanisms of entry of plasma membrane components such as the receptor-ligand complexes and membrane lipids as well as the extracellular fluid into cells. The intracellular sorting and trafficking of these molecules upon internalization are also described. The roles of endocytosis in physiological and pathological processes are discussed. These include maintenance of cell polarization, antigen presentation, glucose transport, atherosclerosis, Alzheimer's disease, and the endocytosis of toxins and viruses.
Store depletion and calcium influx
Authors: Parekh A. B. , Penner R.
Published: December 2017

Calcium influx in nonexcitable cells regulates such diverse processes as exocytosis, contraction, enzyme control, gene regulation, cell proliferation, and apoptosis. The dominant Ca2+ entry pathway in these cells is the store-operated one, in which Ca2+ entry is governed by the Ca2+ content of the agonist-sensitive intracellular Ca2+ stores. Only recently has a Ca2+ current been described that is activated by store depletion. The properties of this new current, called Ca2+ release-activated Ca2+ current (ICRAC), have been investigated in detail using the patch-clamp technique. Despite intense research, the nature of the signal that couples Ca2+ store content to the Ca2+ channels in the plasma membrane has remained elusive. Although ICRAC appears to be the most effective and widespread influx pathway, other store-operated currents have also been observed. Although the Ca2+ release-activated Ca2+ channel has not yet been cloned, evidence continues to accumulate that the Drosophila trp gene might encode a store-operated Ca2+ channel. In this review, we describe the historical development of the field of Ca2+ signaling and the discovery of store-operated Ca2+ currents. We focus on the electrophysiological properties of the prototype store-operated current ICRAC, discuss the regulatory mechanisms that control it, and finally consider recent advances toward the identification of molecular mechanisms involved in this ubiquitous and important Ca2+ entry pathway.
Ion Channels and Early Development of Neural Cells
Authors: TAKAHASHI KUNITARO , OKAMURA YASUSHI
Published: December 2017

Takahashi, Kunitaro, and Yasushi Okamura. Ion Channels and Early Development of Neural Cells. Physiol. Rev. 78: 307–337, 1998. — In this review, we underscore the merits of using voltage-dependent ion channels as markers for neuronal differentiation from the early stages of uncommitted embryonic blastomeres. Furthermore, a fairly large part of the review is devoted to the descriptions of the establishment of a simple model system for neural induction derived from the cleavage-arrested eight-cell ascidian embryo by pairing a single ectodermal with a single vegetal blastomere as a competent and an inducer cell, respectively. The descriptions are focused particularly on the early developmental processes of various ion channels in neuronal and other excitable membranes observed in this extraordinarily simple system, and we compare these results with those in other significant and definable systems for neural differentiation. It is stressed that this simple system, for which most of the electronic and optical methods and various injection experiments are applicable, may be useful for future molecular physiological studies on the intracellular process of differentiation of the early embryonic cells. We have also highlighted the importance of suppressive mechanisms for cellular differentiation from the experimental results, such as epidermal commitment of the cleavage-arrested one-cell Halocynthia embryos or suppression of epidermal-specific transcription of inward rectifier channels by neural induction signals. It was suggested that reciprocal suppressive mechanisms at the transcriptional level may be one of the key processes for cellular differentiation, by which exclusivity of cell types is maintained.
Contributions of Microbes in Vertebrate Gastrointestinal Tract to Production and Conservation of Nutrients
Authors: STEVENS C. EDWARD , HUME IAN D.
Published: December 2017

Stevens, C. Edward, and Ian D. Hume. Contributions of Microbes in Vertebrate Gastrointestinal Tract to Production and Conservation of Nutrients. Physiol. Rev. 78: 393–427, 1998. — The vertebrate gastrointestinal tract is populated by bacteria and, in some species, protozoa and fungi that can convert dietary and endogenous substrates into absorbable nutrients. Because of a neutral pH and longer digesta retention time, the largest bacterial populations are found in the hindgut or large intestine of mammals, birds, reptiles, and adult amphibians and in the foregut of a few mammals and at least one species of bird. Bacteria ferment carbohydrates into short-chain fatty acids (SCFA), convert dietary and endogenous nitrogenous compounds into ammonia and microbial protein, and synthesize B vitamins. Absorption of SCFA provides energy for the gut epithelial cells and plays an important role in the absorption of Na and water. Ammonia absorption aids in the conservation of nitrogen and water. A larger gut capacity and longer digesta retention time provide herbivores with additional SCFA for maintenance energy and foregut-fermenting and copoprophagic hindgut-fermenting species with access to microbially synthesized protein and B vitamins. Protozoa and fungi also contribute nutrients to the host. This review discusses the contributions of gut microorganisms common to all vertebrates, the numerous digestive strategies that allow herbivores to maximize these contributions, and the effects of low-fiber diets and discontinuous feeding schedules on these microbial digestive processes.
Prostanoid Receptors: Structures, Properties, and Functions
Authors: Narumiya Shuh , Sugimoto Yukihiko , Ushikubi Fumitaka
Published: December 2017

Prostanoids are the cyclooxygenase metabolites of arachidonic acid and include prostaglandin (PG) D2, PGE2, PGF2α, PGI2, and thromboxne A2. They are synthesized and released upon cell stimulation and act on cells in the vicinity of their synthesis to exert their actions. Receptors mediating the actions of prostanoids were recently identified and cloned. They are G protein-coupled receptors with seven transmembrane domains. There are eight types and subtypes of prostanoid receptors that are encoded by different genes but as a whole constitute a subfamily in the superfamily of the rhodopsin-type receptors. Each of the receptors was expressed in cultured cells, and its ligand-binding properties and signal transduction pathways were characterized. Moreover, domains and amino acid residues conferring the specificities of ligand binding and signal transduction are being clarified. Information also is accumulating as to the distribution of these receptors in the body. It is also becoming clear for some types of receptors how expression of their genes is regulated. Furthermore, the gene for each of the eight types of prostanoid receptor has been disrupted, and mice deficient in each type of receptor are being examined to identify and assess the roles played by each receptor under various physiological and pathophysiological conditions. In this article, we summarize these findings and attempt to give an overview of the current status of research on the prostanoid receptors.
Mechanisms Controlling the Function and Life Span of the Corpus Luteum
Authors: Niswender Gordon D. , Juengel Jennifer L. , Silva Patrick J. , Rollyson M. Keith , McIntush Eric W.
Published: December 2017

The primary function of the corpus luteum is secretion of the hormone progesterone, which is required for maintenance of normal pregnancy in mammals. The corpus luteum develops from residual follicular granulosal and thecal cells after ovulation. Luteinizing hormone (LH) from the anterior pituitary is important for normal development and function of the corpus luteum in most mammals, although growth hormone, prolactin, and estradiol also play a role in several species. The mature corpus luteum is composed of at least two steroidogenic cell types based on morphological and biochemical criteria and on the follicular source of origin. Small luteal cells appear to be of thecal cell origin and respond to LH with increased secretion of progesterone. LH directly stimulates the secretion of progesterone from small luteal cells via activation of the protein kinase A second messenger pathway. Large luteal cells are of granulosal cell origin and contain receptors for PGF2αand appear to mediate the luteolytic actions of this hormone. If pregnancy does not occur, the corpus luteum must regress to allow follicular growth and ovulation and the reproductive cycle begins again. Luteal regression is initiated by PGF2αof uterine origin in most subprimate species. The role played by PGF2αin primates remains controversial. In primates, if PGF2αplays a role in luteolysis, it appears to be of ovarian origin. The antisteroidogenic effects of PGF2αappear to be mediated by the protein kinase C second messenger pathway, whereas loss of luteal cells appears to follow an influx of calcium, activation of endonucleases, and an apoptotic form of cell death. If the female becomes pregnant, continued secretion of progesterone from the corpus luteum is required to provide an appropriate uterine environment for maintenance of pregnancy. The mechanisms whereby the pregnant uterus signals the corpus luteum that a conceptus is present varies from secretion of a chorionic gonadotropin (primates and equids), to secretion of an antiluteolytic factor (domestic ruminants), and to a neuroendocrine reflex arc that modifies the secretory patterns of hormones from the anterior pituitary (most rodents).
The Voltage Sensor in Voltage-Dependent Ion Channels
Authors: Bezanilla Francisco
Published: December 2017

In voltage-dependent Na, K, or Ca channels, the probability of opening is modified by the membrane potential. This is achieved through a voltage sensor that detects the voltage and transfers its energy to the pore to control its gate. We present here the theoretical basis of the energy coupling between the electric field and the voltage, which allows the interpretation of the gating charge that moves in one channel. Movement of the gating charge constitutes the gating current. The properties are described, along with macroscopic data and gating current noise analysis, in relation to the operation of the voltage sensor and the opening of the channel. Structural details of the voltage sensor operation were resolved initially by locating the residues that make up the voltage sensor using mutagenesis experiments and determining the number of charges per channel. The changes in conformation are then analyzed based on the differential exposure of cysteine or histidine-substituted residues. Site-directed fluorescence labeling is then analyzed as another powerful indicator of conformational changes that allows time and voltage correlation of local changes seen by the fluorophores with the global change seen by the electrophysiology of gating currents and ionic currents. Finally, we describe the novel results on lanthanide-based resonance energy transfer that show small distance changes between residues in the channel molecule. All of the electrophysiological and the structural information are finally summarized in a physical model of a voltage-dependent channel in which a change in membrane potential causes rotation of the S4 segment that changes the exposure of the basic residues from an internally connected aqueous crevice at hyperpolarized potentials to an externally connected aqueous crevice at depolarized potentials.
Creatine and Creatinine Metabolism
Authors: Wyss Markus , Kaddurah-Daouk Rima
Published: December 2017

The goal of this review is to present a comprehensive survey of the many intriguing facets of creatine (Cr) and creatinine metabolism, encompassing the pathways and regulation of Cr biosynthesis and degradation, species and tissue distribution of the enzymes and metabolites involved, and of the inherent implications for physiology and human pathology. Very recently, a series of new discoveries have been made that are bound to have distinguished implications for bioenergetics, physiology, human pathology, and clinical diagnosis and that suggest that deregulation of the creatine kinase (CK) system is associated with a variety of diseases. Disturbances of the CK system have been observed in muscle, brain, cardiac, and renal diseases as well as in cancer. On the other hand, Cr and Cr analogs such as cyclocreatine were found to have antitumor, antiviral, and antidiabetic effects and to protect tissues from hypoxic, ischemic, neurodegenerative, or muscle damage. Oral Cr ingestion is used in sports as an ergogenic aid, and some data suggest that Cr and creatinine may be precursors of food mutagens and uremic toxins. These findings are discussed in depth, the interrelationships are outlined, and all is put into a broader context to provide a more detailed understanding of the biological functions of Cr and of the CK system.
Proteoglycans in the Developing Brain: New Conceptual Insights for Old Proteins
Authors: Bandtlow Christine E. , Zimmermann Dieter R.
Published: December 2017

Proteoglycans are a heterogeneous class of proteins bearing sulfated glycosaminoglycans. Some of the proteoglycans have distinct core protein structures, and others display similarities and thus may be grouped into families such as the syndecans, the glypicans, or the hyalectans (or lecticans). Proteoglycans can be found in almost all tissues being present in the extracellular matrix, on cellular surfaces, or in intracellular granules. In recent years, brain proteoglycans have attracted growing interest due to their highly regulated spatiotemporal expression during nervous system development and maturation. There is increasing evidence that different proteoglycans act as regulators of cell migration, axonal pathfinding, synaptogenesis, and structural plasticity. This review summarizes the most recent data on structures and functions of brain proteoglycans and focuses on new physiological concepts for their potential roles in the developing central nervous system.
Proximal Tubular Phosphate Reabsorption: Molecular Mechanisms
Authors: Murer Heini , Hernando Nati , Forster Ian , Biber Jürg
Published: December 2017

Renal proximal tubular reabsorption of Piis a key element in overall Pihomeostasis, and it involves a secondary active Pitransport mechanism. Among the molecularly identified sodium-phosphate (Na/Pi) cotransport systems a brush-border membrane type IIa Na-Picotransporter is the key player in proximal tubular Pireabsorption. Physiological and pathophysiological alterations in renal Pireabsorption are related to altered brush-border membrane expression/content of the type IIa Na-Picotransporter. Complex membrane retrieval/insertion mechanisms are involved in modulating transporter content in the brush-border membrane. In a tissue culture model (OK cells) expressing intrinsically the type IIa Na-Picotransporter, the cellular cascades involved in “physiological/pathophysiological” control of Pireabsorption have been explored. As this cell model offers a “proximal tubular” environment, it is useful for characterization (in heterologous expression studies) of the cellular/molecular requirements for transport regulation. Finally, the oocyte expression system has permitted a thorough characterization of the transport characteristics and of structure/function relationships. Thus the cloning of the type IIa Na-Picotransporter (in 1993) provided the tools to study renal brush-border membrane Na-Picotransport function/regulation at the cellular/molecular level as well as at the organ level and led to an understanding of cellular mechanisms involved in control of proximal tubular Pihandling and, thus, of overall Pihomeostasis.
Dynamics and Consequences of Potassium Shifts in Skeletal Muscle and Heart During Exercise
Authors: Sejersted Ole M. , Sjøgaard Gisela
Published: December 2017

Since it became clear that K+shifts with exercise are extensive and can cause more than a doubling of the extracellular [K+] ([K+]s) as reviewed here, it has been suggested that these shifts may cause fatigue through the effect on muscle excitability and action potentials (AP). The cause of the K+shifts is a transient or long-lasting mismatch between outward repolarizing K+currents and K+influx carried by the Na+-K+pump. Several factors modify the effect of raised [K+]sduring exercise on membrane potential ( Em) and force production. 1) Membrane conductance to K+is variable and controlled by various K+channels. Low relative K+conductance will reduce the contribution of [K+]sto the Em. In addition, high Cl−conductance may stabilize the Emduring brief periods of large K+shifts. 2) The Na+-K+pump contributes with a hyperpolarizing current. 3) Cell swelling accompanies muscle contractions especially in fast-twitch muscle, although little in the heart. This will contribute considerably to the lowering of intracellular [K+] ([K+]c) and will attenuate the exercise-induced rise of intracellular [Na+] ([Na+]c). 4) The rise of [Na+]cis sufficient to activate the Na+-K+pump to completely compensate increased K+release in the heart, yet not in skeletal muscle. In skeletal muscle there is strong evidence for control of pump activity not only through hormones, but through a hitherto unidentified mechanism. 5) Ionic shifts within the skeletal muscle t tubules and in the heart in extracellular clefts may markedly affect excitation-contraction coupling. 6) Age and state of training together with nutritional state modify muscle K+content and the abundance of Na+-K+pumps. We conclude that despite modifying factors coming into play during muscle activity, the K+shifts with high-intensity exercise may contribute substantially to fatigue in skeletal muscle, whereas in the heart, except during ischemia, the K+balance is controlled much more effectively.
Prolactin: Structure, Function, and Regulation of Secretion
Authors: Freeman Marc E. , Kanyicska Béla , Lerant Anna , Nagy György
Published: December 2017

Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.
Adaptation in Vertebrate Photoreceptors
Authors: Fain Gordon L. , Matthews Hugh R. , Cornwall M. Carter , Koutalos Yiannis
Published: December 2017

When light is absorbed within the outer segment of a vertebrate photoreceptor, the conformation of the photopigment rhodopsin is altered to produce an activated photoproduct called metarhodopsin II or Rh*. Rh*initiates a transduction cascade similar to that for metabotropic synaptic receptors and many hormones; the Rh*activates a heterotrimeric G protein, which in turn stimulates an effector enzyme, a cyclic nucleotide phosphodiesterase. The phosphodiesterase then hydrolyzes cGMP, and the decrease in the concentration of free cGMP reduces the probability of opening of channels in the outer segment plasma membrane, producing the electrical response of the cell. Photoreceptor transduction can be modulated by changes in the mean light level. This process, called light adaptation (or background adaptation), maintains the working range of the transduction cascade within a physiologically useful region of light intensities. There is increasing evidence that the second messenger responsible for the modulation of the transduction cascade during background adaptation is primarily, if not exclusively, Ca2+, whose intracellular free concentration is decreased by illumination. The change in free Ca2+is believed to have a variety of effects on the transduction mechanism, including modulation of the rate of the guanylyl cyclase and rhodopsin kinase, alteration of the gain of the transduction cascade, and regulation of the affinity of the outer segment channels for cGMP. The sensitivity of the photoreceptor is also reduced by previous exposure to light bright enough to bleach a substantial fraction of the photopigment in the outer segment. This form of desensitization, called bleaching adaptation (the recovery from which is known as dark adaptation), seems largely to be due to an activation of the transduction cascade by some form of bleached pigment. The bleached pigment appears to activate the G protein transducin directly, although with a gain less than Rh*. The resulting decrease in intracellular Ca2+then modulates the transduction cascade, by a mechanism very similar to the one responsible for altering sensitivity during background adaptation.
Cellular and Synaptic Adaptations Mediating Opioid Dependence
Authors: Williams John T. , Christie MacDonald J. , Manzoni Olivier
Published: December 2017

Although opioids are highly effective for the treatment of pain, they are also known to be intensely addictive. There has been a massive research investment in the development of opioid analgesics, resulting in a plethora of compounds with varying affinity and efficacy at all the known opioid receptor subtypes. Although compounds of extremely high potency have been produced, the problem of tolerance to and dependence on these agonists persists. This review centers on the adaptive changes in cellular and synaptic function induced by chronic morphine treatment. The initial steps of opioid action are mediated through the activation of G protein-linked receptors. As is true for all G protein-linked receptors, opioid receptors activate and regulate multiple second messenger pathways associated with effector coupling, receptor trafficking, and nuclear signaling. These events are critical for understanding the early events leading to nonassociative tolerance and dependence. Equally important are associative and network changes that affect neurons that do not have opioid receptors but that are indirectly altered by opioid-sensitive cells. Finally, opioids and other drugs of abuse have some common cellular and anatomical pathways. The characterization of common pathways affected by different drugs, particularly after repeated treatment, is important in the understanding of drug abuse.
Sodium-Potassium-Adenosinetriphosphatase-Dependent Sodium Transport in the Kidney: Hormonal Control
Authors: Féraille Eric , Doucet Alain
Published: December 2017

Tubular reabsorption of filtered sodium is quantitatively the main contribution of kidneys to salt and water homeostasis. The transcellular reabsorption of sodium proceeds by a two-step mechanism: Na+-K+-ATPase-energized basolateral active extrusion of sodium permits passive apical entry through various sodium transport systems. In the past 15 years, most of the renal sodium transport systems (Na+-K+-ATPase, channels, cotransporters, and exchangers) have been characterized at a molecular level. Coupled to the methods developed during the 1965–1985 decades to circumvent kidney heterogeneity and analyze sodium transport at the level of single nephron segments, cloning of the transporters allowed us to move our understanding of hormone regulation of sodium transport from a cellular to a molecular level. The main purpose of this review is to analyze how molecular events at the transporter level account for the physiological changes in tubular handling of sodium promoted by hormones. In recent years, it also became obvious that intracellular signaling pathways interacted with each other, leading to synergisms or antagonisms. A second aim of this review is therefore to analyze the integrated network of signaling pathways underlying hormone action. Given the central role of Na+-K+-ATPase in sodium reabsorption, the first part of this review focuses on its structural and functional properties, with a special mention of the specificity of Na+-K+-ATPase expressed in renal tubule. In a second part, the general mechanisms of hormone signaling are briefly introduced before a more detailed discussion of the nephron segment-specific expression of hormone receptors and signaling pathways. The three following parts integrate the molecular and physiological aspects of the hormonal regulation of sodium transport processes in three nephron segments: the proximal tubule, the thick ascending limb of Henle's loop, and the collecting duct.
Nonvertebrate Hemoglobins: Functions and Molecular Adaptations
Authors: Weber Roy E. , Vinogradov Serge N.
Published: December 2017

Hemoglobin (Hb) occurs in all the kingdoms of living organisms. Its distribution is episodic among the nonvertebrate groups in contrast to vertebrates. Nonvertebrate Hbs range from single-chain globins found in bacteria, algae, protozoa, and plants to large, multisubunit, multidomain Hbs found in nematodes, molluscs and crustaceans, and the giant annelid and vestimentiferan Hbs comprised of globin and nonglobin subunits. Chimeric hemoglobins have been found recently in bacteria and fungi. Hb occurs intracellularly in specific tissues and in circulating red blood cells (RBCs) and freely dissolved in various body fluids. In addition to transporting and storing O2and facilitating its diffusion, several novel Hb functions have emerged, including control of nitric oxide (NO) levels in microorganisms, use of NO to control the level of O2in nematodes, binding and transport of sulfide in endosymbiont-harboring species and protection against sulfide, scavenging of O2in symbiotic leguminous plants, O2sensing in bacteria and archaebacteria, and dehaloperoxidase activity useful in detoxification of chlorinated materials. This review focuses on the extensive variation in the functional properties of nonvertebrate Hbs, their O2binding affinities, their homotropic interactions (cooperativity), and the sensitivities of these parameters to temperature and heterotropic effectors such as protons and cations. Whenever possible, it attempts to relate the ligand binding properties to the known molecular structures. The divergent and convergent evolutionary trends evident in the structures and functions of nonvertebrate Hbs appear to be adaptive in extending the inhabitable environment available to Hb-containing organisms.
Biology of Oligodendrocyte and Myelin in the Mammalian Central Nervous System
Authors: Baumann Nicole , Pham-Dinh Danielle
Published: December 2017

Oligodendrocytes, the myelin-forming cells of the central nervous system (CNS), and astrocytes constitute macroglia. This review deals with the recent progress related to the origin and differentiation of the oligodendrocytes, their relationships to other neural cells, and functional neuroglial interactions under physiological conditions and in demyelinating diseases. One of the problems in studies of the CNS is to find components, i.e., markers, for the identification of the different cells, in intact tissues or cultures. In recent years, specific biochemical, immunological, and molecular markers have been identified. Many components specific to differentiating oligodendrocytes and to myelin are now available to aid their study. Transgenic mice and spontaneous mutants have led to a better understanding of the targets of specific dys- or demyelinating diseases. The best examples are the studies concerning the effects of the mutations affecting the most abundant protein in the central nervous myelin, the proteolipid protein, which lead to dysmyelinating diseases in animals and human (jimpy mutation and Pelizaeus-Merzbacher disease or spastic paraplegia, respectively). Oligodendrocytes, as astrocytes, are able to respond to changes in the cellular and extracellular environment, possibly in relation to a glial network. There is also a remarkable plasticity of the oligodendrocyte lineage, even in the adult with a certain potentiality for myelin repair after experimental demyelination or human diseases.
Short-Chain Fatty Acids and Human Colonic Function: Roles of Resistant Starch and Nonstarch Polysaccharides
Authors: Topping David L. , Clifton Peter M.
Published: December 2017

Resistant starch (RS) is starch and products of its small intestinal digestion that enter the large bowel. It occurs for various reasons including chemical structure, cooking of food, chemical modification, and food mastication. Human colonic bacteria ferment RS and nonstarch polysaccharides (NSP; major components of dietary fiber) to short-chain fatty acids (SCFA), mainly acetate, propionate, and butyrate. SCFA stimulate colonic blood flow and fluid and electrolyte uptake. Butyrate is a preferred substrate for colonocytes and appears to promote a normal phenotype in these cells. Fermentation of some RS types favors butyrate production. Measurement of colonic fermentation in humans is difficult, and indirect measures (e.g., fecal samples) or animal models have been used. Of the latter, rodents appear to be of limited value, and pigs or dogs are preferable. RS is less effective than NSP in stool bulking, but epidemiological data suggest that it is more protective against colorectal cancer, possibly via butyrate. RS is a prebiotic, but knowledge of its other interactions with the microflora is limited. The contribution of RS to fermentation and colonic physiology seems to be greater than that of NSP. However, the lack of a generally accepted analytical procedure that accommodates the major influences on RS means this is yet to be established.
Mechanisms of Spreading Depression and Hypoxic Spreading Depression-Like Depolarization
Authors: Somjen George G.
Published: December 2017

Spreading depression (SD) and the related hypoxic SD-like depolarization (HSD) are characterized by rapid and nearly complete depolarization of a sizable population of brain cells with massive redistribution of ions between intracellular and extracellular compartments, that evolves as a regenerative, “all-or-none” type process, and propagates slowly as a wave in brain tissue. This article reviews the characteristics of SD and HSD and the main hypotheses that have been proposed to explain them. Both SD and HSD are composites of concurrent processes. Antagonists of N-methyl-d-aspartate (NMDA) channels or voltage-gated Na+or certain types of Ca2+channels can postpone or mitigate SD or HSD, but it takes a combination of drugs blocking all known major inward currents to effectively prevent HSD. Recent computer simulation confirmed that SD can be produced by positive feedback achieved by increase of extracellular K+concentration that activates persistent inward currents which then activate K+channels and release more K+. Any slowly inactivating voltage and/or K+-dependent inward current could generate SD-like depolarization, but ordinarily, it is brought about by the cooperative action of the persistent Na+current INa,Pplus NMDA receptor-controlled current. SD is ignited when the sum of persistent inward currents exceeds persistent outward currents so that total membrane current turns inward. The degree of depolarization is not determined by the number of channels available, but by the feedback that governs the SD process. Short bouts of SD and HSD are well tolerated, but prolonged depolarization results in lasting loss of neuron function. Irreversible damage can, however, be avoided if Ca2+influx into neurons is prevented.