- Home
- A-Z Publications
- Annual Review of Physiology
- Previous Issues
- Volume 72, 2010
Annual Review of Physiology - Volume 72, 2010
Volume 72, 2010
- Preface
-
-
-
A Conversation with Rita Levi-Montalcini
Vol. 72 (2010), pp. 1–13More LessThere are very few proven theories that exist in biology. One that has stood the test of time is the neurotrophic theory. It explains why only half of the neurons produced early in development are needed to form a functional nervous system. The explanation came from the discovery of nerve growth factors (NGFs), which help nourish neurons, guide their axons to their proper connections, and prevent cell death. Rita Levi-Montalcini, who formulated this idea, celebrated her 100th birthday on April 22, 2009 in Rome. I had the opportunity to interview her at the European Brain Research Institute (EBRI) in September 2008, which forms the basis of this article. Shortly after the interview, Rita attended the International NGF meeting, held in the Upper Galilee region of Israel (Kfar Blum, Israel). Despite her age, she traveled to the meeting by flying to Tel Aviv and taking a 4-h car ride to the conference site. Remarkably, she participated in the meeting by giving a 30-min talk and sponsoring a poster (see Figure 1).
-
-
-
Cell Death in the Pathogenesis of Heart Disease: Mechanisms and Significance
Vol. 72 (2010), pp. 19–44More LessCell death was once viewed as unregulated. It is now clear that at least a portion of cell death is a regulated cell suicide process. This type of death can exhibit multiple morphologies. One of these, apoptosis, has long been recognized to be actively mediated, and many of its underlying mechanisms have been elucidated. Moreover, necrosis, the traditional example of unregulated cell death, is also regulated in some instances. Autophagy is usually a survival mechanism but can occur in association with cell death. Little is known, however, about how autophagic cells die. Apoptosis, necrosis, and autophagy occur in cardiac myocytes during myocardial infarction, ischemia/reperfusion, and heart failure. Pharmacological and genetic inhibition of apoptosis and necrosis lessens infarct size and improves cardiac function in these disorders. The roles of autophagy in ischemia/reperfusion and heart failure are unresolved. A better understanding of these processes and their interrelationships may allow for the development of novel therapies for the major heart syndromes.
-
-
-
Autophagy During Cardiac Stress: Joys and Frustrations of Autophagy
Vol. 72 (2010), pp. 45–59More LessThe study of autophagy has been transformed by the cloning of most genes in the pathway and the introduction of GFP-LC3 as a reporter to allow visual assessment of autophagy. The field of cardiac biology is not alone in attempting to understand the implications of autophagy. The purpose of this review is to address some of the controversies and conundrums associated with the evolving studies of autophagy in the heart. Autophagy is a cellular process involving a complex orchestration of regulatory gene products as well as machinery for assembly, selective targeting, and degradation of autophagosomes and their contents. Our understanding of the role of autophagy in human disease is rapidly evolving as investigators examine the process in different tissues and different pathophysiological contexts. In the field of heart disease, autophagy has been examined in the settings of ischemia and reperfusion, preconditioning, cardiac hypertrophy, and heart failure. This review addresses the role of autophagy in cardioprotection, the balance of catabolism and anabolism, the concept of mitochondrial quality control, and the implications of impaired autophagic flux or frustrated autophagy.
-
-
-
The Cardiac Mitochondrion: Nexus of Stress
Vol. 72 (2010), pp. 61–80More LessThe emergence of mitochondria as critical regulators of cardiac myocyte survival and death has revolutionized the field of cardiac biology. Indeed, it is now well recognized that mitochondrial dysfunction plays a crucial role in the pathogenesis of multiple cardiac diseases. A panoply of mitochondrial proteins/complexes ranging from canonical apoptosis proteins such as Bcl2 and Bax, through the mitochondrial permeability transition pore, to ion channels such as mitochondrial KATP channels and connexin-43 have now been implicated as critical regulators of cardiac cell death. The purpose of this review, therefore, is to focus on these mitochondrial mediators/inhibitors of cell death and to address the specific mechanisms that underlie their ability to influence cardiac pathology.
-
-
-
The FoxO Family in Cardiac Function and Dysfunction
Vol. 72 (2010), pp. 81–94More LessThe Forkhead family of transcription factors mediates many aspects of physiology, including stress response, metabolism, commitment to apoptosis, and development. The Forkhead box subfamily O (FoxO) proteins have garnered particular interest due to their involvement in the modulation of cardiovascular biology. In this review, we discuss the mechanisms of FoxO regulation and outcomes of FoxO signaling under normal and pathological cardiovascular contexts.
-
-
-
Chloride Channels: Often Enigmatic, Rarely Predictable
Vol. 72 (2010), pp. 95–121More LessUntil recently, anion (Cl−) channels have received considerably less attention than cation channels. One reason for this may be that many Cl− channels perform functions that might be considered cell-biological, like fluid secretion and cell volume regulation, whereas cation channels have historically been associated with cellular excitability, which typically happens more rapidly. In this review, we discuss the recent explosion of interest in Cl− channels, with special emphasis on new and often surprising developments over the past five years. This is exemplified by the findings that more than half of the ClC family members are antiporters, and not channels, as was previously thought, and that bestrophins, previously prime candidates for Ca2+-activated Cl− channels, have been supplanted by the newly discovered anoctamins and now hold a tenuous position in the Cl− channel world.
-
-
-
Living in the Now: Physiological Mechanisms to Tolerate a Rapidly Changing Environment
Vol. 72 (2010), pp. 127–145More LessRising atmospheric carbon dioxide has resulted in scientific projections of changes in global temperatures, climate in general, and surface seawater chemistry. Although the consequences to ecosystems and communities of metazoans are only beginning to be revealed, a key to forecasting expected changes in animal communities is an understanding of species' vulnerability to a changing environment. For example, environmental stressors may affect a particular species by driving that organism outside a tolerance window, by altering the costs of metabolic processes under the new conditions, or by changing patterns of development and reproduction. Implicit in all these examples is the foundational understanding of physiological mechanisms and how a particular environmental driver (e.g., temperature and ocean acidification) will be transduced through the animal to alter tolerances and performance. In this review, we highlight examples of mechanisms, focusing on those underlying physiological plasticity, that operate in contemporary organisms as a means to consider physiological responses that are available to organisms in the future.
-
-
-
Light, Time, and the Physiology of Biotic Response to Rapid Climate Change in Animals
Vol. 72 (2010), pp. 147–166More LessExamination of temperate and polar regions of Earth shows that the nonbiological world is exquisitely sensitive to the direct effects of temperature, whereas the biological world is largely organized by light. Herein, we discuss the use of day length by animals at physiological and genetic levels, beginning with a comparative experimental study that shows the preeminent role of light in determining fitness in seasonal environments. Typically, at seasonally appropriate times, light initiates a cascade of physiological events mediating the input and interpretation of day length to the output of specific hormones that ultimately determine whether animals prepare to develop, reproduce, hibernate, enter dormancy, or migrate. The mechanisms that form the basis of seasonal time keeping and their adjustment during climate change are reviewed at the physiological and genetic levels. Future avenues for research are proposed that span basic questions from how animals transition from dependency on tropical cues to temperate cues during range expansions, to more applied questions of species survival and conservation biology during periods of climatic stress.
-
-
-
Locomotion in Response to Shifting Climate Zones: Not So Fast
Vol. 72 (2010), pp. 167–190More LessAlthough a species' locomotor capacity is suggestive of its ability to escape global climate change, such a suggestion is not necessarily straightforward. Species vary substantially in locomotor capacity, both ontogenetically and within/among populations, and much of this variation has a genetic basis. Accordingly, locomotor capacity can and does evolve rapidly, as selection experiments demonstrate. Importantly, even though this evolution of locomotor capacity may be rapid enough to escape changing climate, genetic correlations among traits (often due to pleiotropy) are such that successful or rapid dispersers are often limited in colonization or reproductive ability, which may be viewed as a trade-off. The nuanced assessment of this variation and evolution is reviewed for well-studied models: salmon, flying versus flightless insects, rodents undergoing experimental evolution, and metapopulations of butterflies. This work reveals how integration of physiology with population biology and functional genomics can be especially informative.
-
-
-
Genomic Analyses of Hormone Signaling and Gene Regulation
Edwin Cheung, and W. Lee KrausVol. 72 (2010), pp. 191–218More LessMany cellular signaling pathways ultimately control specific patterns of gene expression in the nucleus through a variety of signal-regulated transcription factors (TFs), including nuclear hormone receptors (NRs). The advent of genomic technologies for examining signal-regulated transcriptional responses and TF binding on a genomic scale has dramatically increased our understanding of the cellular programs that control hormonal signaling and gene regulation. Studies of TFs, especially NRs, using genomic approaches have revealed novel and unexpected features of hormone-regulated transcription, and a global view is beginning to emerge. In this review, we discuss the genomic methodologies that have been applied to the study of hormone-regulated gene expression, the results that have been obtained from using them, and the future prospects for these approaches. Given the wealth of information about hormone-dependent gene regulation by NRs, we have focused this review on the knowledge gained from genomic studies of their function.
-
-
-
Macrophages, Inflammation, and Insulin Resistance
Vol. 72 (2010), pp. 219–246More LessObesity induces an insulin-resistant state in adipose tissue, liver, and muscle and is a strong risk factor for the development of type 2 diabetes mellitus. Insulin resistance in the setting of obesity results from a combination of altered functions of insulin target cells and the accumulation of macrophages that secrete proinflammatory mediators. At the molecular level, insulin resistance is promoted by a transition in macrophage polarization from an alternative M2 activation state maintained by STAT6 and PPARs to a classical M1 activation state driven by NF-κB, AP1, and other signal-dependent transcription factors that play crucial roles in innate immunity. Strategies focused on inhibiting the inflammation/insulin resistance axis that otherwise preserve essential innate immune functions may hold promise for therapeutic intervention.
-
-
-
Structural Overview of the Nuclear Receptor Superfamily: Insights into Physiology and Therapeutics
Vol. 72 (2010), pp. 247–272More LessAs ligand-regulated transcription factors, the nuclear hormone receptors are nearly ideal drug targets, with internal pockets that bind to hydrophobic, drug-like molecules and well-characterized ligand-induced conformational changes that recruit transcriptional coregulators to promoter elements. Yet, due to the multitude of genes under the control of a single receptor, the major challenge has been the identification of ligands with gene-selective actions, impacting disease outcomes through a narrow subset of target genes and not across their entire gene-regulatory repertoire. Here, we summarize the concepts and work to date underlying the development of steroidal and nonsteroidal receptor ligands, including the use of crystal structures, high-throughput screens, and rational design approaches for finding useful therapeutic molecules. Difficulties in finding selective receptor modulators require a more complete understanding of receptor interdomain communications, posttranslational modifications, and receptor-protein interactions that could be exploited for target gene selectivity.
-
-
-
Apical Recycling of the Gastric Parietal Cell H,K-ATPase
John G. Forte, and Lixin ZhuVol. 72 (2010), pp. 273–296More LessThe gastric parietal cell was the first system where a regulated membrane recycling hypothesis was proposed as the principal means for moving molecular transporters between cellular compartments. Upon stimulation, massive membrane flow from an endosomal compartment of tubulovesicle membranes to the apical secretory surface places the ATP-driven pumps in position to secrete a solution of strong acid in collaboration with several other membrane transporters. This review focuses on the membrane recycling pathway and proteins that support the recruitment and redistribution of H,K-ATPase-rich membranes, including those involved in signal transduction, membrane targeting, docking, and fusing, in addition to the integral role of the actin cytoskeleton and its associated proteins in the process of membrane recycling. Although much of the evidence discussed here comes from parietal cell studies, other physiological transport systems, as well as less complex cellular and in vitro models, are examined and cited for generality of principle.
-
-
-
Role of Colonic Short-Chain Fatty Acid Transport in Diarrhea
Vol. 72 (2010), pp. 297–313More LessShort-chain fatty acids (SCFA) are the major anion in stool and are synthesized from nonabsorbed carbohydrate by the colonic microbiota. Nonabsorbed carbohydrate are not absorbed in the colon and induce an osmotically mediated diarrhea; in contrast, SCFA are absorbed by colonic epithelial cells and stimulate Na-dependent fluid absorption via a cyclic AMP–independent process involving apical membrane Na-H, SCFA-HCO3, and Cl-SCFA exchanges. SCFA production represents an adaptive process to conserve calories, fluid, and electrolytes. Inhibition of SCFA synthesis by antibiotics and administration of PEG, a substance that is not metabolized by colonic microbiota, both result in diarrhea. In contrast, increased production of SCFA as a result of providing starch that is relatively resistant to amylase digestion [so-called resistant starch (RS)] to oral rehydration solution (RS-ORS) improves the efficacy of ORS and represents an important approach to improve the effectiveness of ORS in the treatment of acute diarrhea in children under five years of age.
-
-
-
The Biogenesis of Chylomicrons
Vol. 72 (2010), pp. 315–333More LessThe absorption of dietary fat is of increasing concern given the rise of obesity not only in the United States but throughout the developed world. This review explores what happens to dietary fat within the enterocyte. Absorbed fatty acids and monoacylglycerols are required to be bound to intracellular proteins and/or to be rapidly converted to triacylglycerols to prevent cellular membrane disruption. The triacylglycerol produced at the level of the endoplasmic reticulum (ER) is either incorporated into prechylomicrons within the ER lumen or shunted to triacylglycerol storage pools. The prechylomicrons exit the ER in a specialized transport vesicle in the rate-limiting step in the intracellular transit of triacylglycerol across the enterocyte. The prechylomicrons are further processed in the Golgi and are transported to the basolateral membrane via a separate vesicular system for exocytosis into the intestinal lamina propria. Fatty acids and monoacylglycerols entering the enterocyte via the basolateral membrane are also incorporated into triacylglycerol, but the basolaterally entering lipid is much more likely to enter the triacylglycerol storage pool than the lipid entering via the apical membrane.
-
-
-
Integrated Brain Circuits: Astrocytic Networks Modulate Neuronal Activity and Behavior
Vol. 72 (2010), pp. 335–355More LessThe past decade has seen an explosion of research on roles of neuron-astrocyte interactions in the control of brain function. We highlight recent studies performed on the tripartite synapse, the structure consisting of pre- and postsynaptic elements of the synapse and an associated astrocytic process. Astrocytes respond to neuronal activity and neurotransmitters, through the activation of metabotropic receptors, and can release the gliotransmitters ATP, d-serine, and glutamate, which act on neurons. Astrocyte-derived ATP modulates synaptic transmission, either directly or through its metabolic product adenosine. d-serine modulates NMDA receptor function, whereas glia-derived glutamate can play important roles in relapse following withdrawal from drugs of abuse. Cell type–specific molecular genetics has allowed a new level of examination of the function of astrocytes in brain function and has revealed an important role of these glial cells that is mediated by adenosine accumulation in the control of sleep and in cognitive impairments that follow sleep deprivation.
-
-
-
Cellular Maintenance and Repair of the Kidney
Vol. 72 (2010), pp. 357–376More LessThe mammalian kidney is a highly complex organ that requires the precise structural arrangement of multiple cell types for effective function. The need to filter large volumes of plasma at the glomerulus followed by active reabsorption of nearly 99% of that filtrate by the tubules creates vulnerability in both compartments for cell injury. Thus maintenance of cell viability and replacement of those cells that are lost are essential for functional stability of the kidney. This review addresses our current understanding of how cells from the glomerular, tubular, and interstitial compartments arise during development and the manner in which they may be regenerated in the adult organ. In addition, we discuss the data regarding the role of organ-specific and bone marrow–derived stem and progenitor cells in the replacement/repair process, as well as the potential for ex vivo programming of stem cells toward a renal lineage.
-
-
-
Intrarenal Purinergic Signaling in the Control of Renal Tubular Transport
Vol. 72 (2010), pp. 377–393More LessRenal tubular epithelial cells receive hormonal input that regulates volume and electrolyte homeostasis. In addition, numerous intrarenal, local signaling agonists have appeared on the stage of renal physiology. One such system is that of intrarenal purinergic signaling. This system involves all the elements necessary for agonist-mediated intercellular communication. ATP is released from epithelial cells, which activates P2 receptors in the apical and basolateral membrane and thereby modulates tubular transport. Termination of the signal is conducted via the breakdown of ATP to adenosine. Recent far-reaching advances indicate that ATP is often used as a local transmitter for classical sensory transduction. This transmission apparently also applies to sensory functions in the kidney. Locally released ATP is involved in sensing of renal tubular flow or in detecting the distal tubular load of NaCl at the macula densa. This review describes the relevant aspects of local, intrarenal purinergic signaling and outlines its integrative concepts.
-
-
-
The Physiological Significance of the Cardiotonic Steroid/Ouabain-Binding Site of the Na,K-ATPase
Vol. 72 (2010), pp. 395–412More LessThe Na,K-ATPase is the membrane “pump” that generates the Na+ and K+ gradients across the plasma membrane that drives many physiological processes. This enzyme is highly sensitive to inhibition by cardiotonic steroids, most notably the digitalis/ouabain class of compounds, which have been used for centuries to treat congestive heart failure and arrhythmias. The amino acids that constitute the ouabain-binding site are highly conserved across the evolutionary spectrum. This could be fortuitous or could result from this site being conserved because it has an important biological function. New physiological approaches using genetically engineered mice are being used to define the biological significance of the “receptor function” of the Na,K-ATPase and its regulation by potential endogenous cardiotonic steroid-like compounds. These studies extend the reach of earlier studies involving the biochemical purification of endogenous regulatory ligands.
-
-
-
Inducible Innate Resistance of Lung Epithelium to Infection
Vol. 72 (2010), pp. 413–435More LessMost studies of innate immunity have focused on leukocytes such as neutrophils, macrophages, and natural killer cells. However, epithelial cells play key roles in innate defenses that include providing a mechanical barrier to microbial entry, signaling to leukocytes, and directly killing pathogens. Importantly, all these defenses are highly inducible in response to the sensing of microbial and host products. In healthy lungs, the level of innate immune epithelial function is low at baseline. This is indicated by low levels of spontaneous microbial killing and cytokine release, reflecting low constitutive stimulation in the nearly sterile lower respiratory tract when mucociliary clearance mechanisms are functioning effectively. This contrasts with the colon, where bacteria are continuously present and epithelial cells are constitutively activated. Although the surface area of the lungs presents a large target for microbial invasion, activated lung epithelial cells that are closely apposed to deposited pathogens are ideally positioned for microbial killing.
-
-
-
It's Not All Smooth Muscle: Non-Smooth-Muscle Elements in Control of Resistance to Airflow
Vol. 72 (2010), pp. 437–462More LessTo achieve gas exchange, inspired air must pass through an intricate and dynamic tracheobronchial tree. The tree offers resistance to airflow, and increased resistance is the most important functional change in lung disease. Numerous mechanisms contribute to increased resistance by causing airway narrowing, closure, occlusion, and/or obliteration. Although airway smooth muscle (ASM) contraction and shortening are an important cause of increased resistance, non-ASM elements can also contribute. Nonmuscle elements can modify the amount of airway narrowing for any given level of ASM shortening and the amount of shortening for a given level of ASM activation. In this review, we outline the physiological basis for airflow resistance and describe how changes in the lung parenchyma, the airways, and their luminal contents can contribute to increased airflow resistance. A detailed understanding of the mechanisms and consequences of increased airway resistance is vital to our attempts to alleviate the enormous burden of suffering caused by obstructive lung diseases.
-
-
-
Regulation of Endothelial Permeability via Paracellular and Transcellular Transport Pathways
Vol. 72 (2010), pp. 463–493More LessThe endothelium functions as a semipermeable barrier regulating tissue fluid homeostasis and transmigration of leukocytes and providing essential nutrients across the vessel wall. Transport of plasma proteins and solutes across the endothelium involves two different routes: one transcellular, via caveolae-mediated vesicular transport, and the other paracellular, through interendothelial junctions. The permeability of the endothelial barrier is an exquisitely regulated process in the resting state and in response to extracellular stimuli and mediators. The focus of this review is to provide a comprehensive overview of molecular and signaling mechanisms regulating endothelial barrier permeability with emphasis on the cross-talk between paracellular and transcellular transport pathways.
-
-
-
TH17 Cells in Asthma and COPD
Vol. 72 (2010), pp. 495–516More LessAsthma and chronic obstructive pulmonary disease (COPD) represent two classes of chronic obstructive lung disorders that may share some similar immunologic mechanisms of disease. Asthma is a complex human disease characterized by airway hyperresponsiveness (AHR) and inflammation, whereas COPD is marked by progressive emphysematic changes in the lung. Recently it has been shown that advanced COPD is characterized by lymphoid follicles, drawing attention to immunological mechanisms in COPD. Despite numerous studies in mice to elucidate the immunologic mechanisms of asthma, sufficient current treatment options are limited. Clinically, many asthma patients fail to satisfactorily respond to standard steroid therapy, and this type of steroid-resistant, severe asthma has been linked to the presence of neutrophilic inflammation in the lung. The role of neutrophils, macrophages, and their secreted proteases in COPD needs to be better defined. Recently, the T lymphocyte subset TH17 was shown to play a role in regulating neutrophilic and macrophage inflammation in the lung, suggesting a potential role for TH17 cells in severe, steroid-insensitive asthma and COPD.
-
-
-
The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks
Vol. 72 (2010), pp. 517–549More LessMost physiology and behavior of mammalian organisms follow daily oscillations. These rhythmic processes are governed by environmental cues (e.g., fluctuations in light intensity and temperature), an internal circadian timing system, and the interaction between this timekeeping system and environmental signals. In mammals, the circadian timekeeping system has a complex architecture, composed of a central pacemaker in the brain's suprachiasmatic nuclei (SCN) and subsidiary clocks in nearly every body cell. The central clock is synchronized to geophysical time mainly via photic cues perceived by the retina and transmitted by electrical signals to SCN neurons. In turn, the SCN influences circadian physiology and behavior via neuronal and humoral cues and via the synchronization of local oscillators that are operative in the cells of most organs and tissues. Thus, some of the SCN output pathways serve as input pathways for peripheral tissues. Here we discuss knowledge acquired during the past few years on the complex structure and function of the mammalian circadian timing system.
-
-
-
Suprachiasmatic Nucleus: Cell Autonomy and Network Properties
Vol. 72 (2010), pp. 551–577More LessThe suprachiasmatic nucleus (SCN) is the primary circadian pacemaker in mammals. Individual SCN neurons in dispersed culture can generate independent circadian oscillations of clock gene expression and neuronal firing. However, SCN rhythmicity depends on sufficient membrane depolarization and levels of intracellular calcium and cAMP. In the intact SCN, cellular oscillations are synchronized and reinforced by rhythmic synaptic input from other cells, resulting in a reproducible topographic pattern of distinct phases and amplitudes specified by SCN circuit organization. The SCN network synchronizes its component cellular oscillators, reinforces their oscillations, responds to light input by altering their phase distribution, increases their robustness to genetic perturbations, and enhances their precision. Thus, even though individual SCN neurons can be cell-autonomous circadian oscillators, neuronal network properties are integral to normal function of the SCN.
-
-
-
Systems Biology of Mammalian Circadian Clocks
Vol. 72 (2010), pp. 579–603More LessSystems biology is a natural extension of molecular biology; it can be defined as biology after identification of key gene(s). Systems-biological research is a multistage process beginning with (a) the comprehensive identification and (b) quantitative analysis of individual system components and their networked interactions, which lead to the ability to (c) control existing systems toward the desired state and (d) design new ones based on an understanding of the underlying structure and dynamical principles. In this review, we use the mammalian circadian clock as a model system and describe the application of systems-biological approaches to fundamental problems in this model. This application has allowed the identification of transcriptional/posttranscriptional circuits, the discovery of a temperature-insensitive period-determining process, and the discovery of desynchronization of individual clock cells underlying the singularity behavior of mammalian clocks.
-
-
-
Circadian Organization of Behavior and Physiology in Drosophila
Vol. 72 (2010), pp. 605–624More LessCircadian clocks organize behavior and physiology to adapt to daily environmental cycles. Genetic approaches in the fruit fly, Drosophila melanogaster, have revealed widely conserved molecular gears of these 24-h timers. Yet much less is known about how these cell-autonomous clocks confer temporal information to modulate cellular functions. Here we discuss our current knowledge of circadian clock function in Drosophila, providing an overview of the molecular underpinnings of circadian clocks. We then describe the neural network important for circadian rhythms of locomotor activity, including how these molecular clocks might influence neuronal function. Finally, we address a range of behaviors and physiological systems regulated by circadian clocks, including discussion of specific peripheral oscillators and key molecular effectors where they have been described. These studies reveal a remarkable complexity to circadian pathways in this “simple” model organism.
-
-
-
Mammalian Per-Arnt-Sim Proteins in Environmental Adaptation
Vol. 72 (2010), pp. 625–645More LessThe Per-Arnt-Sim (PAS) domain is conserved across the kingdoms of life and found in an ever-growing list of proteins. This domain can bind to and sense endogenous or xenobiotic small molecules such as molecular oxygen, cellular metabolites, or polyaromatic hydrocarbons. Members of this family are often found in pathways that regulate responses to environmental change; in mammals these include the hypoxia, circadian, and dioxin response pathways. These pathways function in development and throughout life to regulate cellular, organ, and whole-organism adaptive responses. Remarkably, in the case of the clock, this adaptation includes anticipation of environmental change. In this review, we summarize the roles of PAS domain–containing proteins in mammals. We provide structural evidence that functionally classifies both known and unknown biological roles. Finally, we discuss the role of PAS proteins in anticipation of and adaptation to environmental change.
-
Previous Volumes
-
Volume 86 (2024)
-
Volume 85 (2023)
-
Volume 84 (2022)
-
Volume 83 (2021)
-
Volume 82 (2020)
-
Volume 81 (2019)
-
Volume 80 (2018)
-
Volume 79 (2017)
-
Volume 78 (2016)
-
Volume 77 (2015)
-
Volume 76 (2014)
-
Volume 75 (2013)
-
Volume 74 (2012)
-
Volume 73 (2011)
-
Volume 72 (2010)
-
Volume 71 (2009)
-
Volume 70 (2008)
-
Volume 69 (2007)
-
Volume 68 (2006)
-
Volume 67 (2005)
-
Volume 66 (2004)
-
Volume 65 (2003)
-
Volume 64 (2002)
-
Volume 63 (2001)
-
Volume 62 (2000)
-
Volume 61 (1999)
-
Volume 60 (1998)
-
Volume 59 (1997)
-
Volume 58 (1996)
-
Volume 57 (1995)
-
Volume 56 (1994)
-
Volume 55 (1993)
-
Volume 54 (1992)
-
Volume 53 (1991)
-
Volume 52 (1990)
-
Volume 51 (1989)
-
Volume 50 (1988)
-
Volume 49 (1987)
-
Volume 48 (1986)
-
Volume 47 (1985)
-
Volume 46 (1984)
-
Volume 45 (1983)
-
Volume 44 (1982)
-
Volume 43 (1981)
-
Volume 42 (1980)
-
Volume 41 (1979)
-
Volume 40 (1978)
-
Volume 39 (1977)
-
Volume 38 (1976)
-
Volume 37 (1975)
-
Volume 36 (1974)
-
Volume 35 (1973)
-
Volume 34 (1972)
-
Volume 33 (1971)
-
Volume 32 (1970)
-
Volume 31 (1969)
-
Volume 30 (1968)
-
Volume 29 (1967)
-
Volume 28 (1966)
-
Volume 27 (1965)
-
Volume 26 (1964)
-
Volume 25 (1963)
-
Volume 24 (1962)
-
Volume 23 (1961)
-
Volume 22 (1960)
-
Volume 21 (1959)
-
Volume 20 (1958)
-
Volume 19 (1957)
-
Volume 18 (1956)
-
Volume 17 (1955)
-
Volume 16 (1954)
-
Volume 15 (1953)
-
Volume 14 (1952)
-
Volume 13 (1951)
-
Volume 12 (1950)
-
Volume 11 (1949)
-
Volume 10 (1948)
-
Volume 9 (1947)
-
Volume 8 (1946)
-
Volume 7 (1945)
-
Volume 6 (1944)
-
Volume 5 (1943)
-
Volume 4 (1942)
-
Volume 3 (1941)
-
Volume 2 (1940)
-
Volume 1 (1939)
-
Volume 0 (1932)