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- Volume 61, 1999
Annual Review of Physiology - Volume 61, 1999
Volume 61, 1999
- Preface
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- Review Articles
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PULLING THE CART AND ENJOYING THE RIDE
Vol. 61 (1999), pp. 1–17More Less▪ AbstractI was pleased to receive the invitation to write this prefatory chapter. In doing so, I join a number of physiologists whose work and writings I have often admired. There are two aspects of my experience in physiology that I discuss here. The first concerns my own research accomplishments. The second is my role in developing three departments of physiology and fostering the careers of others. While I take pleasure in the former, the overall contribution of the latter was undoubtedly greater.
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CELLULAR AND MOLECULAR BASIS FOR ELECTRICAL RHYTHMICITY IN GASTROINTESTINAL MUSCLES
Vol. 61 (1999), pp. 19–43More Less▪ AbstractRegulation of gastrointestinal (GI) motility is intimately coordinated with the modulation of ionic conductances expressed in GI smooth muscle and nonmuscle cells. Interstitial cells of Cajal (ICC) act as pacemaker cells and possess unique ionic conductances that trigger slow wave activity in these cells. The slow wave mechanism is an exclusive feature of ICC: Smooth muscle cells may lack the basic ionic mechanisms necessary to generate or regenerate slow waves. The molecular identification of the components for these conductances provides the foundation for a complete understanding of the ionic basis for GI motility. In addition, this information will provide a basis for the identification or development of therapeutics that might act on these channels. It is much easier to study these conductances and develop blocking drugs in expression systems than in native GI muscle cells. This review focuses on the relationship between ionic currents in native GI smooth muscle cells and ICC and their molecular counterparts.
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IONIC CONDUCTANCES IN GASTROINTESTINAL SMOOTH MUSCLES AND INTERSTITIAL CELLS OF CAJAL
Vol. 61 (1999), pp. 45–84More Less▪ AbstractIon channels are the unitary elements that underlie electrical activity of gastrointestinal smooth muscle cells and of interstitial cells of Cajal. The result of ion channel activity in the gastrointestinal smooth muscle layers is a rhythmic change in membrane potential that in turn underlies events leading to organized motility patterns. Gastrointestinal smooth muscle cells and interstitial cells of Cajal express a wide variety of ion channels that are tightly regulated. This review summarizes 20 years of data obtained from patch-clamp studies on gastrointestinal smooth muscle cells and interstitial cells, with a focus on regulation.
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EXCITATION-CONTRACTION COUPLING IN GASTROINTESTINAL AND OTHER SMOOTH MUSCLES
Vol. 61 (1999), pp. 85–115More Less▪ AbstractThe main contributors to increases in [Ca2+]i and tension are the entry of Ca2+ through voltage-dependent channels opened by depolarization or during action potential (AP) or slow-wave discharge, and Ca2+ release from store sites in the cell by the action of IP3 or by Ca2+-induced Ca2+-release (CICR). The entry of Ca2+ during an AP triggers CICR from up to 20 or more subplasmalemmal store sites (seen as hot spots, using fluorescent indicators); Ca2+ waves then spread from these hot spots, which results in a rise in [Ca2+]i throughout the cell. Spontaneous transient releases of store Ca2+, previously detected as spontaneous transient outward currents (STOCs), are seen as sparks when fluorescent indicators are used. Sparks occur at certain preferred locations—frequent discharge sites (FDSs)—and these and hot spots may represent aggregations of sarcoplasmic reticulum scattered throughout the cytoplasm. Activation of receptors for excitatory signal molecules generally depolarizes the cell while it increases the production of IP3 (causing calcium store release) and diacylglycerols (which activate protein kinases). Activation of receptors for inhibitory signal molecules increases the activity of protein kinases through increases in cAMP or cGMP and often hyperpolarizes the cell. Other receptors link to tyrosine kinases, which trigger signal cascades interacting with trimeric G-protein systems.
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THE ENTERIC NERVOUS SYSTEM AND REGULATION OF INTESTINAL MOTILITY
Vol. 61 (1999), pp. 117–142More Less▪ AbstractThe enteric nervous system exerts local control over mixing and propulsive movements in the small intestine. When digestion is in progress, intrinsic primary afferent neurons (IPANs) are activated by the contents of the intestine. The IPANs that have been physiologically characterized are in the intrinsic myenteric ganglia. They are numerous, about 650/mm length of small intestine in the guinea pig, and communicate with each other through slow excitatory transmission to form self-reinforcing assemblies. High proportions of these neurons respond to chemicals in the lumen or to tension in the muscle; physiological stimuli activate assemblies of hundreds or thousands of IPANs. The IPANs make direct connections with muscle motor neurons and with ascending and descending interneurons. The circular muscle contracts as an annulus, about 2–3 mm in minimum oral-to-anal extent in the guinea pig small intestine. The smooth muscle cells form an electrical syncytium that is innervated by about 300 excitatory and 400 inhibitory motor neurons per mm length. The intrinsic nerve circuits that control mixing and propulsion in the small intestine are now known, but it remains to be determined how they are programmed to generate the motility patterns that are observed.
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MECHANISMS OF CARDIAC PAIN
Vol. 61 (1999), pp. 143–167More Less▪ AbstractAngina pectoris often results from ischemic episodes that excite chemosensitive and mechanoreceptive receptors in the heart. Ischemic episodes release a collage of chemicals, including adenosine and bradykinin, that excites the receptors of the sympathetic and vagal afferent pathways. Sympathetic afferent fibers from the heart enter the upper thoracic spinal cord and synapse on cells of origin of ascending pathways. This review focuses on the spinothalamic tract, but other pathways are excited as well. Excitation of spinothalamic tract cells in the upper thoracic and lower cervical segments, except C7 and C8 segments, contributes to the anginal pain experienced in the chest and arm. Cardiac vagal afferent fibers synapse in the nucleus tractus solitarius of the medulla and then descend to excite upper cervical spinothalamic tract cells. This innervation contributes to the anginal pain experienced in the neck and jaw. The spinothalamic tract projects to the medial and lateral thalamus and, based on positron emission tomography studies, activates several cortical areas, including the anterior cingulate gyrus (BA 24 and 25), the lateral basal frontal cortex, and the mesiofrontal cortex.
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DESENSITIZATION OF G-PROTEIN–COUPLED RECEPTORS IN THE CARDIOVASCULAR SYSTEM
Vol. 61 (1999), pp. 169–192More Less▪ AbstractMultiple mechanisms exist to control the signaling and density of G-protein-coupled receptors (GPRs). Upon agonist binding and receptor activation, a series of reactions participate in the turn off or desensitization of GPRs. Many GPRs are phosphorylated by protein kinases and consequently uncoupled from G proteins. In addition, many GPRs are sequestered from the cell surface and become inaccessible to their activating ligands. Both receptor:G protein uncoupling and receptor sequestration may involve the participation of arrestins or other proteins. A model for receptor regulation has been developed from studies of the β-adrenergic receptor. However, recent studies suggest that other GPRs important in the cardiovascular system, such as the muscarinic cholinergic receptors that regulate heart rate, might be regulated by mechanisms other than those that regulate the β-adrenergic receptors. This review summarizes our current understanding of the processes involved in the desensitization of GPRs.
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REGULATION OF NATRIURETIC PEPTIDE SECRETION BY THE HEART
G. Thibault, F. Amiri, and R. GarciaVol. 61 (1999), pp. 193–217More Less▪ AbstractSecreted by the heart, more specifically by atrial cardiomyocytes under normal conditions but also by ventricular myocytes during cardiac hypertrophy, natriuretic peptides are now considered important hormones in the control of blood pressure and salt and water excretion. Studies on natriuretic peptide secretagogues and their mechanisms of action have been complicated by hemodynamic changes and contractions to which the atria are constantly subjected. It now appears that atrial stretch through mechano-sensitive ion channels, adrenergic stimulation via α1A-adrenergic receptors, and endothelin via its ETA receptor subtype are major triggering agents of natriuretic peptide release. With several other stimuli, such as angiotensin II and β-adrenergic agents, modulation of natriuretic peptide release appears to be linked to local generation of prostaglandins. In all cases, intracellular calcium homeostasis, controlled by several ion channels, is considered a key element in the regulation of natriuretic peptide secretion.
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MYOBLAST CELL GRAFTING INTO HEART MUSCLE: Cellular Biology and Potential Applications
P. D. Kessler, and B. J. ByrneVol. 61 (1999), pp. 219–242More Less▪ AbstractThis review surveys a wide range of cellular and molecular approaches to strengthening the injured or weakened heart, focusing on strategies to replace dysfunctional, necrotic, or apoptotic cardiomyocytes with new cells of mesodermal origin. A variety of cell types, including myogenic cell lines, adult skeletal myoblasts, immortalized atrial cells, embryonic and adult cardiomyocytes, embryonic stem cells, teratoma cells, genetically altered fibroblasts, smooth muscle cells, and bone marrow–derived cells have all been proposed as useful cells in cardiac repair and may have the capacity to perform cardiac work. We focus on the implantation of mesodermally derived cells, the best developed of the options. We review the developmental and cell biology that have stimulated these studies, examine the limitations of current knowledge, and identify challenges for the future, which we believe are considerable.
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HEAT-SHOCK PROTEINS, MOLECULAR CHAPERONES, AND THE STRESS RESPONSE: Evolutionary and Ecological Physiology
Vol. 61 (1999), pp. 243–282More Less▪ AbstractMolecular chaperones, including the heat-shock proteins (Hsps), are a ubiquitous feature of cells in which these proteins cope with stress-induced denaturation of other proteins. Hsps have received the most attention in model organisms undergoing experimental stress in the laboratory, and the function of Hsps at the molecular and cellular level is becoming well understood in this context. A complementary focus is now emerging on the Hsps of both model and nonmodel organisms undergoing stress in nature, on the roles of Hsps in the stress physiology of whole multicellular eukaryotes and the tissues and organs they comprise, and on the ecological and evolutionary correlates of variation in Hsps and the genes that encode them. This focus discloses that (a) expression of Hsps can occur in nature, (b) all species have hsp genes but they vary in the patterns of their expression, (c) Hsp expression can be correlated with resistance to stress, and (d) species' thresholds for Hsp expression are correlated with levels of stress that they naturally undergo. These conclusions are now well established and may require little additional confirmation; many significant questions remain unanswered concerning both the mechanisms of Hsp-mediated stress tolerance at the organismal level and the evolutionary mechanisms that have diversified the hsp genes.
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GENETIC DISEASES AND GENE KNOCKOUTS REVEAL DIVERSE CONNEXIN FUNCTIONS
Vol. 61 (1999), pp. 283–310More Less▪ AbstractIntercellular channels present in gap junctions allow cells to share small molecules and thus coordinate a wide range of behaviors. Remarkably, although junctions provide similar functions in all multicellular organisms, vertebrates and invertebrates use unrelated gene families to encode these channels. The recent identification of the invertebrate innexin family opens up powerful genetic systems to studies of intercellular communication. At the same time, new information on the physiological roles of vertebrate connexins has emerged from genetic studies. Mutations in connexin genes underlie a variety of human diseases, including deafness, demyelinating neuropathies, and lens cataracts. In addition, gene targeting of connexins in mice has provided new insights into connexin function and the significance of connexin diversity.
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LOCALIZED INTRACELLULAR CALCIUM SIGNALING IN MUSCLE: Calcium Sparks and Calcium Quarks
Vol. 61 (1999), pp. 311–335More Less▪ AbstractSubcellularly localized Ca2+ signals in cardiac and skeletal muscle have recently been identified as elementary Ca2+ signaling events. The signals, termed Ca2+ sparks and Ca2+ quarks, represent openings of Ca2+ release channels located in the membrane of the sarcoplasmic reticulum (SR). In cardiac muscle, the revolutionary discovery of Ca2+ sparks has allowed the development of a fundamentally different concept for the amplification of Ca2+ signals by Ca2+-induced Ca2+ release. In such a system, a graded amplification of the triggering Ca2+ signal entering the myocyte via L-type Ca2+ channels is accomplished by a recruitment process whereby individual SR Ca2+ release units are locally controlled by L-type Ca2+ channels. In skeletal muscle, the initial SR Ca2+ release is governed by voltage-sensors but subsequently activates additional Ca2+ sparks by Ca2+-induced Ca2+ release from the SR. Results from studies on elementary Ca2+ release events will improve our knowledge of muscle Ca2+ signaling at all levels of complexity, from the molecule to normal cellular function, and from the regulation of cardiac and skeletal muscle force to the pathophysiology of excitation-contraction coupling.
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ATP-SENSITIVE POTASSIUM CHANNELS: A Model of Heteromultimeric Potassium Channel/Receptor Assemblies
Vol. 61 (1999), pp. 337–362More Less▪ AbstractATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. By cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the receptors for sulfonylureas (SUR1 and SUR2), researchers have clarified the molecular structure of KATP channels. KATP channels comprise two subunits: a Kir6.0 subfamily subunit, which is a member of the inwardly rectifying K+ channel family; and a SUR subunit, which is a member of the ATP-binding cassette (ABC) protein superfamily. KATP channels are the first example of a heteromultimeric complex assembled with a K+ channel and a receptor that are structurally unrelated to each other. Since 1995, molecular biological and molecular genetic studies of KATP channels have provided insights into the structure-function relationships, molecular regulation, and pathophysiological roles of KATP channels.
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ADRENOMEDULLIN AND THE CONTROL OF FLUID AND ELECTROLYTE HOMEOSTASIS
Vol. 61 (1999), pp. 363–389More Less▪ AbstractTwo potent hypotensive peptides, adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP), are encoded by the adrenomedullin gene. AM stimulates nitric oxide production by endothelial cells, whereas PAMP acts presynaptically to inhibit adrenergic nerves that innervate blood vessels. Complementary, but mechanistically unique, actions also occur in the anterior pituitary gland where both peptides inhibit adrenocorticotropin release. In the adrenal gland both AM and PAMP inhibit potassium and angiotensin II-stimulated aldosterone secretion. Natriuretic and diuretic actions of AM reflect unique actions of the peptide on renal blood flow and tubular function. In the brain AM inhibits water intake and, in a physiologically relevant manner, salt appetite. Both AM and PAMP act in the brain to elevate sympathetic tone, effects that mirror the positive inotropic action of AM in the heart. Cardioprotective actions in the brain and heart may be important counter-regulatory actions that buffer the extreme hypotensive actions of the peptides when released in sepsis. Thus the biologic actions of the proadrenomedullin-derived peptides seem well coordinated to contribute to the physiologic regulation of volume and electrolyte homeostasis.
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PATHOPHYSIOLOGY OF ENDOTHELIN IN THE CARDIOVASCULAR SYSTEM
Vol. 61 (1999), pp. 391–415More Less▪ AbstractIn this article, we review the basic pharmacological and biochemical features of endothelin and the pathophysiological roles of endothelin in cardiovascular diseases. Development of receptor antagonists has accelerated the pace of investigations into the pathophysiological roles of endogenous endothelin-1 in various diseases, e.g. chronic heart failure, renal diseases, hypertension, cerebral vasospasm, and pulmonary hypertension. In chronic heart failure, the expression of endothelin-1 and its receptors in cardiomyocytes is increased, and treatment with an endothelin receptor antagonist improves survival and cardiac function. Endothelin receptor antagonists also improve other cardiovascular diseases. These results suggest that the interference with endothelin pathway either by receptor blockade or by inhibition of endothelin converting enzyme may provide novel therapeutic drugs strategies for multiple disease states.
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GENE INTERACTIONS IN GONADAL DEVELOPMENT
Vol. 61 (1999), pp. 417–433More Less▪ AbstractThe acquisition of a sexually dimorphic phenotype is a critical event in mammalian development. Although the maturation of sexual function and reproduction occurs after birth, essentially all of the critical developmental steps take place during embryogenesis. Temporally, these steps can be divided into two different phases: sex determination, the initial event that determines whether the gonads will develop as testes or ovaries; and sexual differentiation, the subsequent events that ultimately produce either the male or the female sexual phenotype. A basic tenet of sexual development in mammals is that genetic sex—determined by the presence or absence of the Y chromosome—directs the embryonic gonads to differentiate into either testes or ovaries. Thereafter, hormones produced by the testes direct the developmental program leading to male sexual differentiation. In the absence of testicular hormones, the pathway of sexual differentiation is female. This chapter reviews the anatomic and cellular changes that constitute sexual differentiation and discusses SRY and other genes, including SF-1, WT1, DAX-1, and SOX9, that play key developmental roles in this process. Dose-dependent interactions among these genes are critical for sex determination and differentiation.
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SYNCHRONOUS ACTIVITY IN THE VISUAL SYSTEM
Vol. 61 (1999), pp. 435–456More Less▪ AbstractSynchronous activity among ensembles of neurons is a robust phenomenon observed in many regions of the brain. With the increased use of multielectrode recording techniques, synchronous firing of ensembles of neurons has been found at all levels in the mammalian visual pathway, from the retina to the extrastriate cortex. Here we distinguish three categories of synchrony in the visual system, (a) synchrony from anatomical divergence, (b) stimulus-dependent synchrony, and (c) emergent synchrony (oscillations). Although all three categories have been well documented, their functional significance remains uncertain. We discuss several lines of evidence both for and against a role for synchrony in visual processing: the perceptual consequences of synchronous activity, its ability to carry information, and the transmission of synchronous neural events to subsequent stages of processing.
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TIMING IN THE AUDITORY SYSTEM OF THE BAT
Vol. 61 (1999), pp. 457–476More Less▪ AbstractEcholocating bats use audition to guide much of their behavior. As in all vertebrates, their lower brainstem contains a number of parallel auditory pathways that provide excitatory or inhibitory outputs differing in their temporal discharge patterns and latencies. These pathways converge in the auditory midbrain, where many neurons are tuned to biologically important parameters of sound, including signal duration, frequency-modulated sweep direction, and the rate of periodic frequency or amplitude modulations. This tuning to biologically relevant temporal patterns of sound is created through the interplay of the time-delayed excitatory and inhibitory inputs to midbrain neurons. Because the tuning process requires integration over a relatively long time period, the rate at which midbrain auditory neurons respond corresponds to the cadence of sounds rather than their fine structure and may provide an output that is closely matched to the rate at which motor systems operate.
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SYNAPTIC MECHANISMS FOR CODING TIMING IN AUDITORY NEURONS
Vol. 61 (1999), pp. 477–496More Less▪ AbstractNeurons in the cochlear ganglion and auditory brain stem nuclei preserve the relative timing of action potentials passed through sequential synaptic levels. To accomplish this task, these neurons have unique morphological and biophysical specializations in axons, dendrites, and nerve terminals. At the membrane level, these adaptations include low-threshold, voltage-gated potassium channels and unusually rapid-acting transmitter-gated channels, which govern how quickly and reliably action potential threshold is reached during a synaptic response. Some nerve terminals are remarkably large and release large amounts of excitatory neurotransmitter. The high output of transmitter at these terminals can lead to synaptic depression, which may itself be regulated by presynaptic transmitter receptors. The way in which these different cellular mechanisms are employed varies in different cell types and circuits and reflects refinements suited to different aspects of acoustic processing.
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THE ROLE OF TIMING IN THE BRAIN STEM AUDITORY NUCLEI OF VERTEBRATES
Vol. 61 (1999), pp. 497–519More Less▪ AbstractVertebrate animals gain biologically important information from environmental sounds. Localization of sound sources enables animals to detect and respond appropriately to danger, and it allows predators to detect and localize prey. In many species, rapidly fluctuating sounds are also the basis of communication between conspecifics. This information is not provided directly by the output of the ear but requires processing of the temporal pattern of firing in the tonotopic array of auditory nerve fibers. The auditory nerve feeds information through several parallel ascending pathways. Anatomical and electrophysiological specializations for conveying precise timing, including calyceal synaptic terminals and matching axonal conduction times, are evident in several of the major ascending auditory pathways through the ventral cochlear nucleus and its nonmammalian homologues. One pathway that is shared by all higher vertebrates makes an ongoing comparison of interaural phase for the localization of sound in the azimuth. Another pathway is specifically associated with higher frequency hearing in mammals and is thought to make use of interaural intensity differences for localizing high-frequency sounds. Balancing excitation from one ear with inhibition from the other in rapidly fluctuating signals requires that the timing of these synaptic inputs be matched and constant for widely varying sound stimuli in this pathway. The monaural nuclei of the lateral lemniscus, whose roles are not understood (although they are ubiquitous in higher vertebrates), receive input from multiple pathways that encode timing with precision, some through calyceal endings.
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TIMING OF SYNAPTIC TRANSMISSION
Vol. 61 (1999), pp. 521–542More Less▪ AbstractMany behaviors require rapid and precisely timed synaptic transmission. These include the determination of a sound's direction by detecting small interaural time differences and visual processing, which relies on synchronous activation of large populations of neurons. In addition, throughout the brain, concerted firing is required by Hebbian learning mechanisms, and local circuits are recruited rapidly by fast synaptic transmission. To achieve speed and precision, synapses must optimize the many steps between the firing of a presynaptic cell and the response of its postsynaptic targets. Until recently, the behavior of mammalian synapses at physiological temperatures was primarily extrapolated from studies at room temperature or from the properties of invertebrate synapses. Recent studies have revealed some of the specializations that make synapses fast and precise in the mammalian central nervous system at physiological temperatures.
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STRUCTURE, STRENGTH, FAILURE, AND REMODELING OF THE PULMONARY BLOOD-GAS BARRIER
Vol. 61 (1999), pp. 543–572More Less▪ AbstractThe pulmonary blood-gas barrier needs to satisfy two conflicting requirements. It must be extremely thin for efficient gas exchange, but also immensely strong to withstand the extremely high stresses in the capillary wall when capillary pressure rises during exercise. The strength of the blood-gas barrier on the thin side is attributable to the type IV collagen in the basement membranes. However, when the wall stresses rise to very high levels, ultrastructural changes in the barrier occur, a condition known as stress failure. Physiological conditions that alter the properties of the barrier include intense exercise in elite human athletes. Some animals, such as Thoroughbred racehorses, consistently break their alveolar capillaries during galloping, causing hemorrhage. Pathophysiological conditions causing stress failure include neurogenic pulmonary edema, high-altitude pulmonary edema, left heart failure, and overinflation of the lung. Remodeling of the capillary wall occurs in response to increased wall stress, a good example being the thickening of the capillary basement membrane in diseases such as mitral stenosis. The blood-gas barrier is able to maintain its extreme thinness with sufficient strength only through continual regulation of its wall structure. Recent experimental work suggests that rapid changes in gene expression for extracellular matrix proteins and growth factors occur in response to increases in capillary wall stress. How the blood-gas barrier is regulated to be extremely thin but sufficiently strong is a central issue in lung biology.
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EVOLUTION OF THE VERTEBRATE CARDIO-PULMONARY SYSTEM
Vol. 61 (1999), pp. 573–592More Less▪ AbstractVertebrate lungs have long been thought to have evolved in fishes largely as an adaptation for life in hypoxic water. This view overlooks the possibility that lungs may have functioned to supply the heart with oxygen and may continue to serve this function in extant fishes. The myocardium of most vertebrates is avascular and obtains oxygen from luminal blood. Because oxygen-rich pulmonary blood mixes with oxygen-poor systemic blood before entering the heart of air-breathing fishes, lung ventilation may supply the myocardium with oxygen and expand aerobic exercise capabilities. Although sustained exercise in tetrapods is facilitated by septation of the heart and the formation of a dual pressure system, a divided cardio-pulmonary system may conflict with myocardial oxygenation because the right side of the heart is isolated from pulmonary oxygen. This may have contributed to the evolution of the coronary circulation.
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MOUSE MODELS OF AIRWAY RESPONSIVENESS: Physiological Basis of Observed Outcomes and Analysis of Selected Examples Using These Outcome Indicators
Vol. 61 (1999), pp. 593–625More Less▪ AbstractThe mouse is an ideal species for investigation at the interface of lung biology and lung function. As detailed in this review, there are well-developed methods for the quantitative study of lung function in mice. These methods can be applied to mice in both terminal and nonterminal experiments. Terminal experimental approaches provide more detailed physiological information, but nonterminal measurements provide adequate data for certain experiments. In this review, we provide two examples of how these models can be used to further understanding of the primary pathobiology of airway responsiveness in both the absence and the presence of induced airway inflammation. The first model is a dissection of chromosomal loci linked to the variance in airway responsiveness observed in the absence of any manipulation to induce airway inflammation. The second model explores the role of T-cell costimulatory signals in the induction of airway hyperresponsiveness. As the number of mice with targeted deletions of effector genes or insertion of informative transgenes grows, additional examples are likely to accrue.
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SODIUM CHANNELS IN ALVEOLAR EPITHELIAL CELLS: Molecular Characterization, Biophysical Properties, and Physiological Significance
Vol. 61 (1999), pp. 627–661More Less▪ AbstractAt birth, fetal distal lung epithelial (FDLE) cells switch from active chloride secretion to active sodium (Na+) reabsorption. Sodium ions Senter the FDLE and alveolar type II (ATII) cells mainly through apical nonselective cation and Na+-selective channels, with conductances of 4–26 pS (picoSiemens) in FDLE and 20–25 pS in ATII cells. All these channels are inhibited by amiloride with a 50% inhibitory concentration of <1 μM, and some are also inhibited by [N-ethyl-N-isopropyl]-2′-4′-amiloride (50% inhibitory concentration of <1 μM). Both FDLE and ATII cells contain the α-, β-, and γ-rENaC (rat epithelial Na+ channels) mRNAs; reconstitution of an ATII cell Na+-channel protein into lipid bilayers revealed the presence of 25-pS Na+ single channels, inhibited by amiloride and [N-ethyl-N-isopropyl]-2′-4′-amiloride. A variety of agents, including cAMP, oxygen, glucocorticoids, and in some cases Ca2+, increased the activity and/or rENaC mRNA levels. The phenotypic properties of these channels differ from those observed in other Na+-absorbing epithelia. Pharmacological blockade of alveolar Na+ transport in vivo, as well as experiments with newborn α-rENaC knock-out mice, demonstrate the importance of active Na+ transport in the reabsorption of fluid from the fetal lung and in reabsorbing alveolar fluid in the injured adult lung. Indeed, in a number of inflammatory diseases, increased production of reactive oxygen-nitrogen intermediates, such as peroxynitrite (ONOO−), may damage ATII and FDLE Na+ channels, decrease Na+ reabsorption in vivo, and thus contribute to the formation of alveolar edema.
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SODIUM-COUPLED TRANSPORTERS FOR KREBS CYCLE INTERMEDIATES
Vol. 61 (1999), pp. 663–682More Less▪ AbstractKrebs cycle intermediates such as succinate, citrate, and α-ketoglutarate are transferred across plasma membranes of cells by secondary active transporters that couple the downhill movement of sodium to the concentrative uptake of substrate. Several transporters have been identified in isolated membrane vesicles and cells based on their functional properties, suggesting the existence of at least three or more Na+/dicarboxylate cotransporter proteins in a given species. Recently, several cDNAs, called NaDC-1, coding for the low-affinity Na+/dicarboxylate cotransporters have been isolated from rabbit, human, and rat kidney. The Na+/dicarboxylate cotransporters are part of a distinct gene family that includes the renal and intestinal Na+/sulfate cotransporters. Other members of this family include a Na+- and Li+-dependent dicarboxylate transporter from Xenopus intestine and a putative Na+/dicarboxylate cotransporter from rat intestine. The current model of secondary structure in NaDC-1 contains 11 transmembrane domains and an extracellular N-glycosylated carboxy terminus.
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MODULATION OF VASOPRESSIN-ELICITED WATER TRANSPORT BY TRAFFICKING OF AQUAPORIN2-CONTAINING VESICLES1
Vol. 61 (1999), pp. 683–697More Less▪ AbstractVasopressin or AVP regulates water reabsorption by the kidney inner medullary collecting duct (IMCD) through the insertion and removal of aquaporin (AQP) 2 water channels into the IMCD apical membrane. AVP-elicited trafficking of AQP2 with the apical membrane occurs via a specialized population of vesicles that resemble synaptic vesicles in neurons. AQP2 vesicles and the IMCD apical membrane contain homologs of vesicle-targeting and signal transduction proteins found in neurons. Expression studies of AQP2, including human AQP2 mutants, suggest that the carboxyl-terminal domain of AQP2 is important in AQP2 trafficking, particularly as a site for cAMP-dependent protein kinase phosphorylation. These present data reveal that IMCD cells possess a complex integrated-signaling and vesicle-trafficking machinery that provides integration of AVP-elicited water transport with many other parameters within the IMCD cell as well as kidney.
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ELECTROGENIC Na+/HCO−3 COTRANSPORTERS: Cloning and Physiology
Vol. 61 (1999), pp. 699–723More Less▪ AbstractBicarbonate and CO2 comprise the major pH buffer of biological fluids. In the renal proximal tubule most of the filtered HCO−3 is reabsorbed by an electrogenic Na/HCO3 cotransporter located at the basolateral membrane. This Na+ bicarbonate cotransporter (NBC) was recently cloned. This review highlights the recent developments leading to and since the cloning of NBC: NBC expression cloning, protein features, clone physiology, isoforms and genes, mRNA distribution, and protein distribution. With the NBC amino acid sequence 30–35% identical to the anion exchangers (AE1-3), a superfamily of HCO−3 transporters is emerging. Physiologically, NBC is electrogenic, Na+ dependent, HCO−3 dependent, Cl− independent, and inhibited by stilbenes (DIDS and SITS). NBC clones and proteins have been isolated from several tissues (other than kidney) thought to have physiologically distinct HCO−3 transporters. For example, NBC occurs in pancreas, prostate, brain, heart, small and large intestine, stomach, and epididymis. Finally, there are at least two genes that encode NBC proteins. Possible future directions of research are discussed.
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ELECTROPHYSIOLOGY OF SYNAPTIC VESICLE CYCLING
Vol. 61 (1999), pp. 725–752More Less▪ AbstractPatch-clamp capacitance measurements can monitor in real time the kinetics of exocytosis and endocytosis in living cells. We review the application of this technique to the giant presynaptic terminals of goldfish bipolar cells. These terminals secrete glutamate via the fusion of small, clear-core vesicles at specialized, active zones of release called synaptic ribbons. We compare the functional characteristics of transmitter release at ribbon-type and conventional synapses, both of which have a unique capacity for fast and focal vesicle fusion. Subsequent rapid retrieval and recycling of fused synaptic vesicle membrane allow presynaptic terminals to function independently of the cell soma and, thus, as autonomous computational units. Together with the mobilization of reserve vesicle pools, local cycling of synaptic vesicles may delay the onset of vesicle pool depletion and sustain neuronal output during high stimulation frequencies.
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GENETICS OF SYNAPTIC VESICLE FUNCTION: Toward the Complete Functional Anatomy of an Organelle
Vol. 61 (1999), pp. 753–776More Less▪ AbstractSynaptic transmission starts with the release of neurotransmitters by exocytosis of synaptic vesicles. As a relatively simple organelle with a limited number of components, synaptic vesicles are in principle accessible to complete structural and functional genetic analysis. At present, the majority of synaptic vesicle proteins has been characterized, and many have been genetically analyzed in mice, Drosophila, and Caenorhabditis elegans. These studies have shown that synaptic vesicles contain proteins with diverse structures and functions. Although the genetic studies are as yet unfinished, they promise to lead to a full description of synaptic vesicles as macromolecular machines involved in all aspects of presynaptic neurotransmitter release.
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RECONSTITUTION OF REGULATED EXOCYTOSIS IN CELL-FREE SYSTEMS: A Critical Appraisal
Vol. 61 (1999), pp. 777–807More Less▪ AbstractRegulated exocytosis involves the tightly controlled fusion of a transport vesicle with the plasma membrane. It includes processes as diverse as the release of neurotransmitters from presynaptic nerve endings and the sperm-triggered deposition of a barrier preventing polyspermy in oocytes. Cell-free model systems have been developed for studying the biochemical events underlying exocytosis. They range from semi-intact permeabilized cells to the reconstitution of membrane fusion from isolated secretory vesicles and their target plasma membranes. Interest in such cell-free systems has recently been reinvigorated by new evidence suggesting that membrane fusion is mediated by a basic mechanism common to all intracellular fusion events. In this chapter, we review some of the literature in the light of these new developments and attempt to provide a critical discussion of the strengths and limitations of the various cell-free systems.
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MECHANISMS OF HAIR CELL TUNING
R. Fettiplace, and P. A. FuchsVol. 61 (1999), pp. 809–834More Less▪ AbstractMechanosensory hair cells of the vertebrate inner ear contribute to acoustic tuning through feedback processes involving voltage-gated channels in the basolateral membrane and mechanotransduction channels in the apical hair bundle. The specific number and kinetics of calcium-activated (BK) potassium channels determine the resonant frequency of electrically tuned hair cells. Kinetic variation among BK channels may arise through alternative splicing of slo gene mRNA and combination with modulatory β subunits. The number of transduction channels and their rate of adaptation rise with hair cell response frequency along the cochlea's tonotopic axis. Calcium-dependent feedback onto transduction channels may underlie active hair bundle mechanics. The relative contributions of electrical and mechanical feedback to active tuning of hair cells may vary as a function of sound frequency.
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ION CHANNELS OF NOCICEPTION
Vol. 61 (1999), pp. 835–856More Less▪ AbstractNociceptors are the first cells in the series of neurons that lead to the sensation of pain. The essential functions of nociceptors—transducing noxious stimuli into depolarizations that trigger action potentials, conducting the action potentials from the peripheral sensory site to the synapse in the central nervous system, and converting the action potentials into neurotransmitter release at the presynaptic terminal—all depend on ion channels. This review discusses recent results in the converging fields of nociception and ion channel biology. It focuses on (a) the capsaicin receptor and its possible role in thermosensation, (b) ATP-gated channels, (c) proton-gated channels, and (d) nociceptor-specific Na+ channels.
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CONTROVERSIAL ISSUES IN VERTEBRATE OLFACTORY TRANSDUCTION
Vol. 61 (1999), pp. 857–871More Less▪ AbstractA number of controversial issues in olfactory transduction are discussed including the matter of multiple transduction pathways, with a new experiment proposed. Evidence is reviewed concerning the fact that cyclic AMP is the only pathway mediating olfactory transduction. Two knockout mice have been produced: a knockout for a cyclic nucleotide-gated channel and a Golf knockout. The results obtained with both mice are consistent with cyclic AMP being the only second messenger. The evidence for gaseous second channel messengers is also reviewed. Slow gating kinetics of the cyclic nucleotide-gated channel and the detection of single-odorant molecules are reviewed. A new phenomenon in which odorants can block odorant responses is discussed.
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CELLULAR MECHANISMS OF TASTE TRANSDUCTION
Vol. 61 (1999), pp. 873–900More Less▪ AbstractTaste receptor cells respond to gustatory stimuli using a complex arrangement of receptor molecules, signaling cascades, and ion channels. When stimulated, these cells produce action potentials that result in the release of neurotransmitter onto an afferent nerve fiber that in turn relays the identity and intensity of the gustatory stimuli to the brain. A variety of mechanisms are used in transducing the four primary tastes. Direct interaction of the stimuli with ion channels appears to be of particular importance in transducing stimuli reported as salty or sour, whereas the second messenger systems cyclic AMP and inositol trisphosphate are important in transducing bitter and sweet stimuli. In addition to the four basic tastes, specific mechanisms exist for the amino acid glutamate, which is sometimes termed the fifth primary taste, and for fatty acids, a so-called nonconventional taste stimulus. The emerging picture is that not only do individual taste qualities use more than one mechanism, but multiple pathways are available for individual tastants as well.
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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 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 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 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)