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- Volume 62, 2000
Annual Review of Physiology - Volume 62, 2000
Volume 62, 2000
- Preface
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- Review Articles
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Ventricular Fibrillation: Mechanisms of Initiation and Maintenance
Vol. 62 (2000), pp. 25–50More Less▪ AbstractVentricular fibrillation (VF) is the major immediate cause of sudden cardiac death. Traditionally, VF has been defined as turbulent cardiac electrical activity, which implies a large amount of irregularity in the electrical waves that underlie ventricular excitation. During VF, the heart rate is too high (> 550 excitations/minute) to allow adequate pumping of blood. In the electrocardiogram (ECG), ventricular complexes that are ever-changing in frequency, contour, and amplitude characterize VF. This article reviews prevailing theories for the initiation and maintenance of VF, as well as its spatio-temporal organization. Particular attention is given to recent experiments and computer simulations suggesting that VF may be explained in terms of highly periodic three-dimensional rotors that activate the ventricles at exceedingly high frequency. Such rotors may show at least two different behaviors: (a) At one extreme, they may drift throughout the heart at high speeds producing beat-to-beat changes in the activation sequence. (b) At the other extreme, rotors may be relatively stationary, activating the ventricles at such high frequencies that the wave fronts emanating from them breakup at varying distances, resulting in complex spatio-temporal patterns of fibrillatory conduction. In either case, the recorded ECG patterns are indistinguishable from VF. The data discussed have paved the way for a better understanding of the mechanisms of VF in the normal, as well as the diseased, human heart.
When the heart is diseased, its work is imperfectly performed: the vessels proceeding from the heart become inactive, so that you cannot feel them … If the heart trembles, has little power and sinks, the disease is advancing and death is near.
Ebers Papyrus ∼3500 BC
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Basic Mechanisms of Atrial Fibrillation—Very New Insights into Very Old Ideas
Vol. 62 (2000), pp. 51–77More Less▪ AbstractAtrial fibrillation (AF) was recognized and studied extensively in the early twentieth century, but many fundamental aspects of the arrhythmia were poorly understood until quite recently. It is now recognized that AF can be initiated by a variety of mechanisms that share the ability to cause extremely rapid, irregular atrial electrical activity. Once initiated, AF causes alterations in atrial electrical properties (electrical remodeling), including both rapid functional changes and slower alterations in ion channel gene expression, which promote the maintenance of AF and facilitate reinitiation of the arrhythmia should it terminate. Electrical remodeling decreases the atrial refractory period in a heterogeneous way, thus decreasing the size and stability of potential functional atrial reentry waves and promoting multiple-circuit reentry. Whatever the initial cause of AF, electrical remodeling is likely to be a final common pathway that ultimately supervenes. Recent advances in understanding ion channel function, regulation, and remodeling at the molecular level have allowed for a much more detailed appreciation of the basic determinants of AF. Improvements in the clinical management of AF will inevitably follow the recent advances in our understanding of its detailed pathophysiology.
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Ischemic Preconditioning: From Adenosine Receptor to KATP Channel
Vol. 62 (2000), pp. 79–109More Less▪ AbstractIschemic preconditioning is a phenomenon whereby exposure of the myocardium to a brief episode of ischemia and reperfusion markedly reduces tissue necrosis induced by a subsequent prolonged ischemia. It is hoped that elucidation of the mechanism for preconditioning will yield therapeutic strategies capable of reducing myocardial infarction. In the rabbit, the brief period of preconditioning ischemia and reperfusion releases adenosine, bradykinin, opioids, and oxygen radicals. The combined effect of the release of these substances on G proteins and the cell’s phospholipases induces the translocation and activation of the ε isozyme of protein kinase C.
Protein kinase C appears to be the first element of a complex kinase cascade that is activated during the prolonged ischemia in preconditioned hearts. Current evidence indicates that this cascade contains at least one tyrosine kinase and ultimately leads to the activation of p38 mitogen-activated protein kinase. p38 Mitogen-activated protein kinase phosphorylates mitogen-activated protein kinase-activated protein kinase 2. Mitogen-activated protein kinase-activated protein kinase 2 phosphorylates HSP27, a 27-kDa heat shock protein that controls actin filament polymerization, and, therefore, affects the integrity of the cytoskeleton. Finally, mitochondrial adenosine 5′-triphosphate-sensitive K+ channels open, and the latter may be the final mediator of protection for ischemic preconditioning. The protective pathway has many builtin redundancies, perhaps creating a safety factor. These redundancies may also explain some of the species-related differences seen in ischemic preconditioning in which one redundant pathway may predominate over another.
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Sodium-Calcium Exchange: A Molecular Perspective
Vol. 62 (2000), pp. 111–133More Less▪ AbstractPlasma membrane Na+-Ca2+ exchange is an essential component of Ca2+ signaling pathways in several tissues. Activity is especially high in the heart where the exchanger is an important regulator of contractility. An expanding exchanger superfamily includes three mammalian Na+-Ca2+ exchanger genes and a number of alternative splicing products. New information indicates that the exchanger protein has nine transmembrane segments. The exchanger, which transports Na+ and Ca2+, is also regulated by these substrates. Some molecular information is available on regulation by Na+ and Ca2+ and by PIP2 and phosphorylation. Altered expression of the exchanger in pathophysiological states may contribute to various cardiac phenotypes. Use of transgenic approaches is beginning to improve our knowledge of exchanger function.
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The Evolutionary Physiology of Animal Flight: Paleobiological and Present Perspectives
Vol. 62 (2000), pp. 135–155More Less▪ AbstractRecent geophysical analyses suggest the presence of a late Paleozoic oxygen pulse beginning in the late Devonian and continuing through to the late Carboniferous. During this period, plant terrestrialization and global carbon deposition resulted in a dramatic increase in atmospheric oxygen levels, ultimately yielding concentrations potentially as high as 35% relative to the contemporary value of 21%. Such hyperoxia of the late Paleozoic atmosphere may have physiologically facilitated the initial evolution of insect flight metabolism. Widespread gigantism in late Paleozoic insects and other arthropods is also consistent with enhanced oxygen flux within diffusion-limited tracheal systems. Because total atmospheric pressure increases with increased oxygen partial pressure, concurrently hyperdense conditions would have augmented aerodynamic force production in early forms of flying insects. By the late Permian, evolution of decompositional microbial and fungal communities, together with disequilibrium in rates of carbon deposition, gradually reduced oxygen concentrations to values possibly as low as 15%. The disappearance of giant insects by the end of the Permian is consistent with extinction of these taxa for reasons of asphyxiation on a geological time scale. As with winged insects, the multiple historical origins of vertebrate flight in the late Jurassic and Cretaceous correlate temporally with periods of elevated atmospheric oxygen. Much discussion of flight performance in Archaeopteryx assumes a contemporary atmospheric composition. Elevated oxygen levels in the mid- to late Mesozoic would, however, have facilitated aerodynamic force production and enhanced muscle power output for ancestral birds, as well as for precursors to bats and pterosaurs.
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Variability in the Size, Composition, and Function of Insect Flight Muscles
Vol. 62 (2000), pp. 157–178More Less▪ AbstractIn order to fly, insects require flight muscles that constitute at least 12 to 16% of their total mass, and flight performance increases as this percentage increases. However, flight muscles are energetically and materially expensive to build and maintain, and investment in flight muscles constrains other aspects of function, particularly female fecundity. This review examines ways in which insects vary the size of their flight muscles, and how variation in the relative size and composition of flight muscles affects flight performance. Sources of variability in flight muscle size and composition include genetic differences within and between species, individual phenotypic responses to environmental stimuli, and maturational changes that occur before and during the adult stage. Insects have evolved a wide variety of ways to adjust flight muscle size and contractile performance in order to meet demands imposed by variation in life history and ecology.
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Flight Respiration and Energetics
Vol. 62 (2000), pp. 179–205More Less▪ AbstractWe use a comparative approach to examine some of the physiological traits that make flight possible. Comparisons of related fliers and runners suggest that fliers generally have higher aerobic metabolic capacities than runners but that the difference is highly dependent on the taxa studied. The high metabolic rates of fliers relative to runners, especially in insects, are correlated with high locomotory muscle cycle frequencies and low efficiences of conversion of metabolic power to mechanical power. We examine some factors that produce variation in flight respiration and energetics. Air temperature strongly affects the flight metabolic rate of some insects and birds. Flight speed interacts with flier mass, so that small fliers tend to exhibit a Jshaped power curve and larger fliers a U-shaped power curve. As body size increases, mass-specific aerobic flight metabolism decreases in most studies, but mass-specific power output is constant or increases, leading to an increase in efficiency with size. Intraspecific studies have revealed specific genetically based effects on flight metabolism and power output and multiple ecological correlates of flight capabilities.
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Mechanisms Underlying the Cost of Living in Animals
Vol. 62 (2000), pp. 207–235More Less▪ AbstractThe cost of living can be measured as an animal’s metabolic rate. Basal metabolic rate (BMR) is factorially related to other metabolic rates. Analysis of BMR variation suggests that metabolism is a series of linked processes varying in unison. Membrane processes, such as maintenance of ion gradients, are important costs and components of BMR. Membrane bilayers in metabolically active systems are more polyunsaturated and less monounsaturated than metabolically less-active systems. Such polyunsaturated membranes have been proposed to result in an increased molecular activity of membrane proteins, and in this manner the amount of membrane and its composition can act as a pacemaker for metabolism. The potential importance of membrane acyl composition in metabolic depression, hormonal control of metabolism, the evolution of endothermy, as well as its implications for lifespan and human health, are briefly discussed.
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Functional Consequences of Altering Myocardial Adrenergic Receptor Signaling
Vol. 62 (2000), pp. 237–260More Less▪ AbstractFrom the ability to successfully manipulate the mouse genome has come important transgenic and gene-targeted knockout models that impact many areas of biomedical research. Genetically engineered mouse models geared toward the study of cardiovascular regulation have recently been described and provide powerful tools to study normal and compromised cardiac physiology. The genetic manipulation of the adrenergic receptor (AR) signaling system in the heart, including its regulation by desensitizing kinases, has shed light on the role of this signaling pathway in the regulation of cardiac contractility. One major finding, supported by several mouse models, is that in vivo contractility can be enhanced via alteration of myocardial AR signaling. Thus genetic manipulation of this critical receptor system in the heart represents a novel therapeutic approach for improving function of the failing heart.
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Remodeling the Cardiac Sarcomere Using Transgenesis
Vol. 62 (2000), pp. 261–287More Less▪ AbstractAn underpinning of basic physiology and clinical medicine is that specific protein complements underlie cell and organ function. In the heart, contractile protein changes correlating with functional alterations occur during both normal development and the development of numerous pathologies. What has been lacking for the majority of these observations is an extension of correlation to causative proof. More specifically, different congenital heart diseases are characterized by shifts in the motor proteins, and the genetic etiologies of a number of different dilated and hypertrophic cardiomyopathies have been established as residing at loci encoding the contractile proteins. To establish cause, or to understand development of the pathophysiology over an animal’s life span, it is necessary to direct the heart to synthesize, in the absence of other pleiotropic changes, the candidate protein. Subsequently one can determine whether or how the protein’s presence causes the effects either directly or indirectly. By affecting the heart’s protein complement in a defined manner, the potential to establish the function of different proteins and protein isoforms exists. Transgenesis provides a means of stably modifying the mammalian genome. By directing expression of engineered proteins to the heart, cardiac contractile protein profiles can be effectively remodeled and the resultant animal used to study the consequences of a single, genetic manipulation at the molecular, biochemical, cytological, and physiological levels.
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Genetic Dissection of Cardiac Growth Control Pathways
Vol. 62 (2000), pp. 289–320More Less▪ AbstractCardiac muscle cells exhibit two related but distinct modes of growth that are highly regulated during development and disease. Cardiac myocytes rapidly proliferate during fetal life but exit the cell cycle irreversibly soon after birth, following which the predominant form of growth shifts from hyperplastic to hypertrophic. Much research has focused on identifying the candidate mitogens, hypertrophic agonists, and signaling pathways that mediate these processes in isolated cells. What drives the proliferative growth of embryonic myocardium in vivo and the mechanisms by which adult cardiac myocytes hypertrophy in vivo are less clear. Efforts to answer these questions have benefited from rapid progress made in techniques to manipulate the murine genome. Complementary technologies for gain- and loss-of-function now permit a mutational analysis of these growth control pathways in vivo in the intact heart. These studies have confirmed the importance of suspected pathways, have implicated unexpected pathways as well, and have led to new paradigms for the control of cardiac growth.
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Genetically Engineered Models with Alterations in Cardiac Membrane Calcium-Handling Proteins
Vol. 62 (2000), pp. 321–351More Less▪ AbstractRegulation of intracellular Ca2+ provides a means by which the strength and duration of cardiac muscle contraction is altered on a beat-to-beat basis. Ca2+ homeostasis is maintained by proteins of the outer cell membrane or sarcolemma and the sarcoplasmic reticulum, which is the major intracellular Ca2+ storage organelle. Recently, genetic engineering techniques designed to induce specific mutations, manipulate expression levels, or change a particular isoform of various membrane Ca2+-handling proteins have provided novel approaches in elucidating the physiological role of these gene products in the mammalian heart. This review summarizes findings in murine genetic models with alterations in the expression levels of the sarcolemmal Ca2+-ATPase and Na+/Ca2+ exchanger, which move Ca2+ across the cell membrane, and the sarcoplasmic reticulum proteins, which are involved in Ca2+ sequestration (Ca2+-ATPase and its regulator, phospholamban), Ca2+ storage (calsequestrin), and Ca2+ release (ryanodine receptor, FK506-binding protein and junctin) during excitation-contraction coupling. Advances in genetic technology, coupled with the development of miniaturized technology to assess cardiac function at multiple levels in the mouse, have added a wealth of new information to our understanding of the functional role of each of these membrane Ca2+-handling proteins in cardiac physiology and pathophysiology. Furthermore, these genetic models have provided valuable insights into the compensatory cross-talk mechanisms between the major membrane Ca2+-handling proteins in the mammalian heart.
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Diapause
M. B. Renfree, and G. ShawVol. 62 (2000), pp. 353–375More Less▪ AbstractEmbryonic diapause, or delayed implantation as it is sometimes known, is said to occur when the conceptus enters a state of suspended animation at the blastocyst stage of development. Blastocysts may either cease cell division so that their size and cell numbers remain constant, or undergo a period of very slow growth with minimal cell division and expansion. Diapause has independently evolved on many occasions. There are almost 100 mammals in seven different mammalian orders that undergo diapause. In some groups, such as rodents, kangaroos, and mustelids, it is widespread, whereas others such as the Artiodactyla have only a single representative (the roe deer). In each family the characteristics of diapause differ, and the specific controls vary widely from lactational to seasonal, from estrogen to progesterone, or from photoperiod to nutritional. Prolactin is a key hormone controlling the endocrine milieu of diapause in many species, but paradoxically it may act either to stimulate or inhibit growth and activity of the corpus luteum. Whatever the speciesspecific mechanisms, the ecological result of diapause is one of synchronization: It effectively lengthens the active gestation period, which allows mating to occur and young to be born at times of the year optimal for that species.
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Multiple Endocrine Neoplasias
A. O. Hoff, G. J. Cote, and R. F. GagelVol. 62 (2000), pp. 377–411More Less▪ AbstractThe multiple endocrine neoplasia syndromes form a distinct group of genetic tumor syndromes. They include multiple endocrine neoplasia types 1 and 2, von Hippel Lindau syndrome, neurofibromatosis, and Carney complex. Research over the past decade has identified a molecular basis for each of these syndromes. This knowledge has revolutionized not only the clinical management but also has illuminated the field of human cancer research by the identification of new and important genes critical for regulation of cell growth, differentiation, and death. This review focuses on the structure, physiologic function, and molecular abnormalities of the genes involved in these syndromes.
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Leptin
Vol. 62 (2000), pp. 413–437More Less▪ AbstractThe discovery of the adipose-derived hormone leptin has generated enormous interest in the interaction between peripheral signals and brain targets involved in the regulation of feeding and energy balance. Plasma leptin levels correlate with fat stores and respond to changes in energy balance. It was initially proposed that leptin serves a primary role as an anti-obesity hormone, but this role is commonly thwarted by leptin resistance. Leptin also serves as a mediator of the adaptation to fasting, and this role may be the primary function for which the molecule evolved. There is increasing evidence that leptin has systemic effects apart from those related to energy homeostasis, including regulation of neuroendocrine and immune function and a role in development.
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The Mechanism of Action of Thyroid Hormones
Vol. 62 (2000), pp. 439–466More Less▪ AbstractThyroid hormone is essential for normal development, differentiation, and metabolic balance. Thyroid hormone action is mediated by multiple thyroid hormone receptor isoforms derived from two distinct genes. The thyroid hormone receptors belong to a nuclear receptor superfamily that also includes receptors for other small lipophilic hormones. Thyroid hormone receptors function by binding to specific thyroid hormone-responsive sequences in promoters of target genes and by regulating transcription. Thyroid hormone receptors often form heterodimers with retinoid X receptors. Heterodimerization is regulated through distinct mechanisms that together determine the specificity and flexibility of the sequence recognition. Amino-terminal regions appear to modulate thyroid hormone receptor function in an isoform-dependent manner. Unliganded thyroid hormone receptor represses transcription through recruitment of a corepressor complex, which also includes Sin3A and histone deacetylase. Ligand binding alters the conformation of the thyroid hormone receptor in such a way as to release the corepressor complex and recruit a coactivator complex that includes multiple histone acetyltransferases, including a steroid receptor family coactivator, p300/CREB-binding protein–associated factor (PCAF), and CREB binding protein (CBP). The existence of histone-modifying activities in the transcriptional regulatory complexes indicates an important role of chromatin structure. Stoichiometric, structural, and sequence-specific rules for coregulator interaction are beginning to be understood, as are aspects of the tissue specificity of hormone action. Moreover, knockout studies suggest that the products of two thyroid hormone receptor genes mediate distinct functions in vivo. The increased understanding of the structure and function of thyroid hormone receptors and their interacting proteins has markedly clarified the molecular mechanisms of thyroid hormone action.
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Role of CFTR in the Colon
Vol. 62 (2000), pp. 467–491More Less▪ AbstractIn contrast to the airways, the defects in colonic function in cystic fibrosis (CF) patients are closely related to the defect in CFTR. The gastrointestinal phenotype of CF transgenic mice closely resembles the phenotype in CF patients, which clearly indicates the crucial role of CFTR in colonic Cl− secretion and the absence of an effective compensation.
In the colon, stimulation of CFTR Cl− channels involves cAMP- or cGMPdependent phosphorylation. Exocytosis is not involved. Activation of CFTR leads to coactivation of basolateral KVLQT1-type K+ channels and inhibition of luminal Na+ channels (ENaC). In contrast to cultured cells, Ca2+ does not activate luminal Cl− channels in intact enterocytes. It activates basolateral SK4-type K+ channels and luminal K+ channels, which provide additional driving force for Cl− exit. The magnitude of Cl− secretion, however, completely depends on the presence of at least a residual CFTR function in the luminal membrane.
These findings have been clearly demonstrated by Ussing chamber experiments in colon epithelium biopsies of CF and normal individuals: Colonic Cl− secretion in CF patients is variable and reflects the genotype; a complete defect of CFTR is paralleled by the absence of Cl− secretion and unmasks Ca2+-regulated K+ channels in the luminal membrane; overabsorption of Na+ in CF reflects the absence of ENaC inhibition by CFTR; and the functional status of CF colon can be mimicked by the complete suppression of cAMP stimulation in enterocytes of healthy individuals.
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Intracellular Ca2+ and Cl– Channel Activation in Secretory Cells
J. F. Kidd, and P. ThornVol. 62 (2000), pp. 493–513More Less▪ AbstractMolecular and functional evidence indicates that a variety of Ca2+dependent chloride (Cl(Ca)) channels are involved in fluid secretion from secretory epithelial cells in different tissues and species. Most Cl(Ca) channels so far characterized have an I− permeability greater than Cl−, and most are sensitive to 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS). Whole-cell Cl(Ca) currents show outward rectification. Single-channel current voltage relationships are linear with conductances ranging from 2 to 30 pS. Some Cl(Ca) channels are blocked by Ca2+-calmodulin-dependent protein kinase (CAMKII) inhibitors. Others, such as the Cl(Ca) channels of parotid and submandibular acinar cells, appear to be directly regulated by Ca2+. In native cells, the Cl(Ca) channels are located on the apical plasma membrane and activated by localized mechanisms of Ca2+ release. This positioning allows the Cl(Ca) channel to respond specifically to localized Ca2+ signals that do not invade other regions of the cell. The Cl(Ca) follows the rising phase of the Ca2+ signal, but in the falling phase hysteresis occurs where the Cl(Ca) current decays more rapidly than the underlying Ca2+. The future elucidation of the identity and mechanisms of regulation of Cl(Ca) channels will be critical to our understanding of stimulus-secretion coupling.
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The Na-K-Cl Cotransporter of Secretory Epithelia
Vol. 62 (2000), pp. 515–534More Less▪ AbstractThe Na-K-Cl cotransporters are a class of ion transport proteins that transport Na, K, and Cl ions into and out of cells in an electrically neutral manner, in most cases with a stoichiometry of 1Na:1K:2Cl. To date, two Na-K-Cl cotransporter isoforms have been identified: NKCC1, which is present in a wide variety of secretory epithelia and non-epithelial cells; and NKCC2, which is present exclusively in the kidney, in the epithelial cells of the thick ascending limb of Henle’s loop and of the macula densa. Both NKCC isoforms represent part of a diverse family of cationchloride cotransport proteins that share a common predicted membrane topology; this family also includes Na-Cl cotransporters and multiple K-Cl cotransporter isoforms. In secretory epithelia, the regulation of NKCC1, which is typically present on the basolateral membrane, is tightly coordinated with that of other transporters, including apical Cl channels, to maintain cell volume and integrity during active salt and fluid secretion. Changes in intracellular [Cl] ([Cl]i) appear to be involved in this regulation of NKCC1, which is directly phosphorylated by an unknown protein kinase in response to various secretagogues as well as reductions in [Cl]i and cell volume. This review focuses on structure-function relationships within NKCC1 and on recent developments pertaining to NKCC1 regulation at cellular and molecular levels.
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Chloride Secretion by the Intestinal Epithelium: Molecular Basis and Regulatory Aspects
Vol. 62 (2000), pp. 535–572More Less▪ AbstractChloride secretion is the major determinant of mucosal hydration thoughout the gastrointestinal tract, and chloride transport is also pivotal in the regulation of fluid secretion by organs that drain into the intestine. Moreover, there are pathological consequences if chloride secretion is either reduced or increased such as in cystic fibrosis and secretory diarrhea, respectively. With the molecular cloning of many of the proteins and regulatory factors that make up the chloride secretory mechanism, there have been significant advances in our understanding of this process at the cellular level. Similarly, emerging data have clarified the intercellular relationships that govern the extent of chloride secretion. The goal of our article is to review this area of investigation, with an emphasis on recent developments and their implications for the physiology and pathophysiology of chloride transport.
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Structure and Regulation of Amiloride-Sensitive Sodium Channels
Vol. 62 (2000), pp. 573–594More Less▪ AbstractAmiloride-sensitive Na+ channels constitute a new class of proteins known as the ENaC-Deg family of ion channels. All members in this family share a common protein structure but differ in their ion selectivity, their affinity for the blocker amiloride, and in their gating mechanisms. These channels are expressed in many tissues of invertebrate and vertebrate organisms where they serve diverse functions varying from Na+ absorption across epithelia to being the receptors for neurotransmitters in the nervous system. Here, we review progress made during the last years in the characterization, regulation, and cloning of new amiloride-sensitive Na+ channels.
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Branching Morphogenesis During Kidney Development
M. Pohl, R. O. Stuart, H. Sakurai, and S. K. NigamVol. 62 (2000), pp. 595–620More Less▪ AbstractEpithelial tissues such as kidney, lung, and breast arise through branching morphogenesis of a pre-existing epithelial structure. They share common morphological stages and a need for regulation of a similar set of developmental decisions—where to start; when, where, and in which direction to branch; and how many times to branch—decisions requiring regulation of cell proliferation, apoptosis, invasiveness, and cell motility. It is likely that similar molecular mechanisms exist for the epithelial branching program. Here we focus on the development of the collecting system of the kidney, where, from recent data using embryonic organ culture, cell culture models of branching morphogenesis, and targeted gene deletion experiments, the outlines of a working model for branching morphogenesis begin to emerge. Key branching morphogenetic molecules in this model include growth factors, transcription factors, distal effector molecules (such as extracellular matrix proteins, integrins, proteinases and their inhibitors), and genes regulating apoptosis and cell proliferation.
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Intrarenal Dopamine: A Key Signal in the Interactive Regulation of Sodium Metabolism
Vol. 62 (2000), pp. 621–647More Less▪ AbstractThe kidney regulates sodium metabolism with extraordinary precision and sensitivity. This is accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between anti-natriuretic and natriuretic factors. Dopamine, produced in renal proximal tubule cells, plays a central role in this interactive network. Natriuretic hormones that are released from extrarenal sources, such as atrial natriuretic peptide, mediate some of their effects via renal dopamine receptors. On the level of the tubules, dopamine acts by opposing the effects of anti-natriuretic factors, such as angiotensin II and α-adrenergic receptors. Sodium retention leads to an increase in renal dopamine tonus, and the natriuretic effects of dopamine are more prominent under this condition. Inhibition or down-regulation of dopamine receptors significantly attenuates the natriuretic response to salt loading. Renal dopamine is modulated by the supply of filtered L-DOPA and the metabolism of dopamine via catechol-O-methyldopamine. The importance of dopamine as a natriuretic hormone is reflected by its capacity to inhibit the majority of renal tubule sodium transporters. Notably, the activity of Na+,K+ATPase is inhibited in most tubule segments by dopamine. Recent studies have elucidated many of the signaling pathways for renal dopamine receptors. Novel principles for homologous and heterologous sensitization of dopamine receptors have been detected that may explain some of the interaction between dopamine and other first messengers that modulate renal tubule sodium transport. A broad understanding of the renal dopamine system has become increasingly important, since there is now strong evidence from both clinical and experimental studies that dysregulation of the renal dopamine system plays a role in many forms of multigenetic hypertension.
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Endothelial Signal Integration in Vascular Assembly
Vol. 62 (2000), pp. 649–671More Less▪ AbstractRegulated assembly of a highly specialized interconnecting network of vascular endothelial and supportive cells is fundamental to embryonic development and organogenesis, as well as to postnatal tissue repair in metazoans. This review advances an “endotheliocentric” model that defines tasks required of endothelial cells and describes molecular controls that regulate steps in activation, assembly, and maturation of new vessels. In addition to the classical assembly mechanisms—angiogenesis and vasculogenesis—endothelial cells are also recruited into vascular structures from the circulatory system in adult animals and from resident mesenchymally derived progenitors during organogenesis of kidney and other organs. Paracrine signaling cascades regulated by hypoxia initiate a sequentially coordinated series of endothelial responses, including matrix degradation, migration, proliferation, and morphogenetic remodeling. Surface receptors on committed endothelial lineage progenitors transduce cues from extracellular-matrix–associated proteins and cell-cell contact to direct migration, matrix attachment, proliferation, targeting and cell-cell assembly, and vessel maturation. Through their capacity to spatially segregate and temporally integrate a diverse range of extracellular signals, endothelial cells determine their migratory paths, cellular partners, and life-or-death responses to local cues.
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Mechanisms of Guanylin Action Via Cyclic GMP in the Kidney
Vol. 62 (2000), pp. 673–695More Less▪ AbstractGuanylin, uroguanylin, and lymphoguanylin are small peptides that activate cell-surface guanylate cyclase receptors and influence cellular function via intracellular cGMP. Guanylins activate two receptors, GC-C and OK-GC, which are expressed in intestine and/or kidney. Elevation of cGMP in the intestine elicits an increase in electrolyte and water secretion. Activation of renal receptors by uroguanylin stimulates urine flow and excretion of sodium, chloride, and potassium. Intracellular cGMP pathways for guanylins include activation of PKG-II and/or indirect stimulation of PKA-II. The result is activation of CFTR and/or ClC-2 channel proteins to enhance the electrogenic secretion of chloride and bicarbonate. Similar cellular mechanisms may be involved in the renal responses to guanylin peptides. Uroguanylin serves as an intestinal natriuretic hormone in postprandial states, thus linking the digestive and renal organ systems in a novel endocrine axis. Therefore, uroguanylin participates in the complex physiological processes underlying the saliuresis that is elicited by a salty meal.
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The Human Language Faculty as an Organ
Vol. 62 (2000), pp. 697–722More Less▪ AbstractDevelopments in the study of language and cognition give increasing credibility to the view that human knowledge of natural language results from—and is made possible by—a biologically determined capacity specific both to this domain and to our species. The functional properties of this capacity develop along a regular maturational path, such that it seems more appropriate to speak of knowledge of our own language as growing rather than as being learned. That our learning of language results from a specific innate capacity rather than by general mechanisms of induction is supported by the extent to which we can be shown to know things that we could not have learned from observation of any plausible available teaching. The domainspecificity of the language faculty is supported by the many dissociations that can be observed between control of language structure and other cognitive functions. Finally, the species-specificity of the human language faculty is supported by the observation that (absent severe pathology) every human child exposed in even limited ways to the triggering experience of linguistic data develops a full, rich capacity that is essentially homogeneous with that of the surrounding community. Efforts to teach human language to other species, however, have uniformly failed. These considerations make it plausible that human language arises in biologically based ways that are quite comparable to those directing other aspects of the structure of the organism. The language organ, in this sense, can be interpreted in a functional sense, and not as implying an anatomical location comparable to that of, say, the kidney.
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Neural Adaptation in the Generation of Rhythmic Behavior
Vol. 62 (2000), pp. 723–753More Less▪ AbstractMotor systems can adapt rapidly to changes in external conditions and to switching of internal goals. They can also adapt slowly in response to training, alterations in the mechanics of the system, and any changes in the system resulting from injury. This article reviews the mechanisms underlying short- and long-term adaptation in rhythmic motor systems. The neuronal networks underlying the generation of rhythmic motor patterns (central pattern generators; CPGs) are extremely flexible. Neuromodulators, central commands, and afferent signals all influence the pattern produced by a CPG by altering the cellular and synaptic properties of individual neurons and the coupling between different populations of neurons. This flexibility allows the generation of a variety of motor patterns appropriate for the mechanical requirements of different forms of a behavior. The matching of motor output to mechanical requirements depends on the capacity of pattern-generating networks to adapt to slow changes in body mechanics and persistent errors in performance. Afferent feedback from body and limb proprioceptors likely plays an important role in driving these long-term adaptive processes.
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Ligand-Gated Ion Channel Interactions with Cytoskeletal and Signaling Proteins
Vol. 62 (2000), pp. 755–778More Less▪ AbstractIn recent years, it has become apparent that ligand-gated ion channels (ionotropic receptors) in the neuronal plasma membrane interact via their cytoplasmic domains with a multitude of intracellular proteins. Different classes of ligand-gated channels associate with distinct sets of intracellular proteins, often through specialized scaffold proteins containing PDZ domains. These specific interactions link the receptor channel to the cortical cytoskeleton and to appropriate signal transduction pathways in the cell. Thus ionotropic receptors are components of extensive protein complexes that are likely involved in the subcellular targeting, cytoskeletal anchoring, and localized clustering of the receptors at specific sites on the neuronal surface. In addition to structural functions, receptor-associated proteins can play important roles as activity modulators or downstream effectors of ligand-gated channels.
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Insights from Mouse Models into the Molecular Basis of Neurodegeneration
N. Heintz, and H. Y. ZoghbiVol. 62 (2000), pp. 779–802More Less▪ AbstractThanks largely to cloning the genes for several neurodegenerative diseases over the past decade and the existence of mouse mutants, the molecular basis of neurodegeneration is finally beginning to yield some of its secrets. We discuss what has been learned about the pathogenesis of “triplet repeat” diseases through mouse models for spinocerebellar ataxia types 1 and 3 and Huntington disease, including the roles of nuclear aggregates and protein cleavage. We also discuss the neurologic phenotypes that arise from mutations in neurotransmitter receptors (lurcher mice) and ion channels (weaver, leaner, and tottering mice), drawing parallels between ischemic cell death and the neurodegeneration that occurs in the lurcher mouse. Finally, we discuss common mechanisms of cell death and lessons learned from these mouse models that might have broader relevance to other neurologic disorders.
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Spatial Considerations for Stimulus-Dependent Transcription in Neurons
Vol. 62 (2000), pp. 803–823More Less▪ AbstractMost neurons have elaborate dendrites as well as an axon emanating from the cell body that form synaptic connections with one or many target cells, which may be located a considerable distance from the cell body. Such complex and impressive morphologies allow some types of neurons to integrate inputs from one to many thousands of pre-synaptic partners and to rapidly propagate electrical signals, often over long distances, to post-synaptic target cells. Much slower, non-electrical signals also propagate from dendrites and distal axons to neuronal nuclei that influence survival, growth, and plasticity. The distances between distal dendrites and/or distal axons and cell bodies of neurons can be hundreds of microns to more than one meter. This long-range biochemical signal propagation from distal dendrites and distal axons to neuronal nuclei is entirely unique to neurons. This review is focused on excitatory neurotransmitter signaling from dendritic synapses to neuronal nuclei as well as on retrograde growth factor signaling from distal axons to neuronal nuclei.
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Lung Development and Function in Preterm Infants in the Surfactant Treatment Era
Vol. 62 (2000), pp. 825–846More Less▪ AbstractMortality of infants of <1-kg birth weight has decreased because of surfactant treatments, antenatal glucocorticoid treatments, and new ventilation strategies. However, many of these infants develop a chronic lung disease characterized by an arrest of lung development and interference with alveolarization. Antenatal glucocorticoids can induce early lung maturation clinically, but new information from transgenic and other experimental models indicates that traditional explanations for glucocorticoid effects on the developing lung are inadequate. These very preterm infants have lungs with small lung gas volumes and delicate lung tissue that are susceptible to injury with the initiation of ventilation and subsequent ventilation. Antenatal proinflammatory exposures are frequent in very preterm infants, and postnatal injury is associated with elevations of proinflammatory cytokines in the lungs. One hypothesis is that proinflammatory cytokines can promote or interfere with lung development as well as promote lung injury. Mechanisms of lung injury being characterized in the adult lung may have unique characteristics in the developing lung.
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Ventilatory Responses to Changes in Temperature in Mammals and Other Vertebrates
Vol. 62 (2000), pp. 847–874More Less▪ AbstractThis article reviews the relationship between pulmonary ventilation (v̇e) and metabolic rate (oxygen consumption) during changes in ambient temperature. The main focus is on mammals, although for comparative purposes the v̇e responses of ectothermic vertebrates are also discussed. First, the effects of temperature on pulmonary mechanics, chemoreceptors, and airway receptors are summarized. Then we review the main v̇e responses to cold and warm stimuli and their interaction with exercise, hypoxia, or hypercapnia. In these cases, mammals attempt to maintain both oxygenation and body temperature, although conflicts can arise because of the respiratory heat loss associated with the increase in ventilation. Finally, we consider the v̇e responses of mammals when body temperature changes, as during torpor, fever, sleep, and hypothermia. In ectotherms, during changes in temperature, v̇e control becomes part of a general strategy to maintain constant relative alkalinity and ensure a constancy of pH-dependent protein functions (alphastat regulation). In mammals on the other hand, v̇e control is aimed to balance metabolic needs with homeothermy. Therefore, alphastat regulation in mammals seems to have a low priority, and it may be adopted only in exceptional cases.
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Role of Transcription Factors in Fetal Lung Development and Surfactant Protein Gene Expression
Vol. 62 (2000), pp. 875–915More Less▪ AbstractBranching morphogenesis of the lung and differentiation of specialized cell populations is dependent upon reciprocal interactions between epithelial cells derived from endoderm of embryonic foregut and surrounding mesenchymal cells. These interactions are mediated by elaboration and concerted actions of a variety of growth and differentiation factors binding to specific receptors. Such factors include members of the fibroblast growth factor family, sonic hedgehog, members of the transforming growth factor-β family, epidermal growth factor, and members of the platelet-derived growth factor family. Hormones that increase cyclic AMP formation, glucocorticoids, and retinoids also play important roles in branching morphogenesis, alveolar development, and cellular differentiation. Expression of the genes encoding these morphogens and their receptors is controlled by a variety of transcription factors that also are highly regulated. Several of these transcription factors serve dual roles as regulators of genes involved in early lung development and in specialized functions of differentiated cells. Targeted null mutations of genes encoding many of these morphogens and transcription factors have provided important insight into their function during lung development. In this chapter, the cellular and molecular mechanisms that control lung development are considered, as well as those that regulate expression of the genes encoding the surfactant proteins.
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Previous Volumes
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Volume 86 (2024)
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Volume 85 (2023)
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Volume 84 (2022)
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Volume 83 (2021)
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Volume 82 (2020)
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Volume 81 (2019)
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Volume 80 (2018)
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Volume 79 (2017)
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Volume 78 (2016)
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Volume 77 (2015)
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Volume 76 (2014)
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Volume 75 (2013)
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Volume 74 (2012)
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Volume 73 (2011)
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Volume 72 (2010)
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Volume 71 (2009)
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Volume 70 (2008)
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Volume 69 (2007)
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Volume 68 (2006)
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Volume 67 (2005)
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Volume 66 (2004)
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Volume 65 (2003)
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Volume 64 (2002)
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Volume 63 (2001)
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Volume 62 (2000)
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Volume 61 (1999)
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Volume 60 (1998)
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Volume 59 (1997)
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Volume 58 (1996)
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Volume 57 (1995)
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Volume 56 (1994)
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Volume 55 (1993)
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Volume 54 (1992)
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Volume 53 (1991)
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Volume 52 (1990)
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Volume 50 (1988)
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Volume 46 (1984)
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Volume 45 (1983)
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Volume 44 (1982)
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Volume 43 (1981)
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Volume 42 (1980)
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Volume 41 (1979)
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Volume 40 (1978)
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Volume 39 (1977)
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Volume 38 (1976)
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Volume 37 (1975)
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Volume 36 (1974)
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Volume 35 (1973)
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Volume 34 (1972)
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Volume 33 (1971)
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Volume 32 (1970)
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Volume 31 (1969)
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Volume 30 (1968)
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Volume 29 (1967)
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Volume 28 (1966)
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Volume 27 (1965)
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Volume 26 (1964)
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Volume 25 (1963)
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Volume 24 (1962)
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Volume 23 (1961)
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Volume 22 (1960)
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Volume 21 (1959)
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Volume 20 (1958)
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Volume 7 (1945)
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Volume 6 (1944)
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Volume 5 (1943)
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Volume 4 (1942)
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Volume 3 (1941)
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Volume 2 (1940)
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Volume 1 (1939)
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Volume 0 (1932)