- Home
- A-Z Publications
- Annual Review of Physiology
- Previous Issues
- Volume 77, 2015
Annual Review of Physiology - Volume 77, 2015
Volume 77, 2015
- Preface
-
-
-
A Conversation with Oliver Smithies
Vol. 77 (2015), pp. 1–11More LessProfessor Oliver Smithies is the Weatherspoon Eminent Distinguished Professor of Pathology and Laboratory Medicine at the University of North Carolina, Chapel Hill. Along with Mario Capecchi and Martin Evans, Oliver was awarded the Nobel Prize in Medicine in Physiology or Medicine in 2007 for his contributions to the development of gene targeting using homologous recombination in embryonic stem cells. This technique has had an immense impact on biomedical research over the past two decades. Professor Smithies has had a long and distinguished career as a researcher and mentor. Here, he provides an entertaining and enlightening discussion of his life in science.
-
-
-
Exosomes: Vehicles of Intercellular Signaling, Biomarkers, and Vectors of Cell Therapy
Vol. 77 (2015), pp. 13–27More LessMesenchymal stem cells (MSCs), whose mechanism of action is predominantly paracrine, are being widely tested for the treatment of a variety of human diseases. No one factor has been proven sufficient to mediate the therapeutic effects of MSCs. However, exosomes—membrane vesicles secreted by many cells, including MSCs—are appealing candidates as vectors of their efficacy. Exosomes can transport and deliver a large cargo of proteins, lipids, and nucleic acids and can modify cell and organ function. In addition to their key role as vehicles of intercellular communication, exosomes are increasingly recognized as biomarkers and prognosticators of disease. Moreover, they have the potential to be used as vehicles of gene and drug delivery for clinical application. This article reviews the biogenesis of exosomes, their molecular composition, and their role as messengers of intercellular communication, focusing on their potential as therapeutic vectors for stem cell therapy.
-
-
-
Mechanisms of Ventricular Arrhythmias: From Molecular Fluctuations to Electrical Turbulence
Zhilin Qu, and James N. WeissVol. 77 (2015), pp. 29–55More LessVentricular arrhythmias have complex causes and mechanisms. Despite extensive investigation involving many clinical, experimental, and computational studies, effective biological therapeutics are still very limited. In this article, we review our current understanding of the mechanisms of ventricular arrhythmias by summarizing the state of knowledge spanning from the molecular scale to electrical wave behavior at the tissue and organ scales and how the complex nonlinear interactions integrate into the dynamics of arrhythmias in the heart. We discuss the challenges that we face in synthesizing these dynamics to develop safe and effective novel therapeutic approaches.
-
-
-
Lysosomal Physiology
Haoxing Xu, and Dejian RenVol. 77 (2015), pp. 57–80More LessLysosomes are acidic compartments filled with more than 60 different types of hydrolases. They mediate the degradation of extracellular particles from endocytosis and of intracellular components from autophagy. The digested products are transported out of the lysosome via specific catabolite exporters or via vesicular membrane trafficking. Lysosomes also contain more than 50 membrane proteins and are equipped with the machinery to sense nutrient availability, which determines the distribution, number, size, and activity of lysosomes to control the specificity of cargo flux and timing (the initiation and termination) of degradation. Defects in degradation, export, or trafficking result in lysosomal dysfunction and lysosomal storage diseases (LSDs). Lysosomal channels and transporters mediate ion flux across perimeter membranes to regulate lysosomal ion homeostasis, membrane potential, catabolite export, membrane trafficking, and nutrient sensing. Dysregulation of lysosomal channels underlies the pathogenesis of many LSDs and possibly that of metabolic and common neurodegenerative diseases.
-
-
-
Phosphoinositide Control of Membrane Protein Function: A Frontier Led by Studies on Ion Channels
Vol. 77 (2015), pp. 81–104More LessAnionic phospholipids are critical constituents of the inner leaflet of the plasma membrane, ensuring appropriate membrane topology of transmembrane proteins. Additionally, in eukaryotes, the negatively charged phosphoinositides serve as key signals not only through their hydrolysis products but also through direct control of transmembrane protein function. Direct phosphoinositide control of the activity of ion channels and transporters has been the most convincing case of the critical importance of phospholipid-protein interactions in the functional control of membrane proteins. Furthermore, second messengers, such as [Ca2+]i, or posttranslational modifications, such as phosphorylation, can directly or allosterically fine-tune phospholipid-protein interactions and modulate activity. Recent advances in structure determination of membrane proteins have allowed investigators to obtain complexes of ion channels with phosphoinositides and to use computational and experimental approaches to probe the dynamic mechanisms by which lipid-protein interactions control active and inactive protein states.
-
-
-
Hedgehog Signaling and Steroidogenesis
Vol. 77 (2015), pp. 105–129More LessSince its discovery nearly 30 years ago, the Hedgehog (Hh) signaling pathway has been shown to be pivotal in many developmental and pathophysiological processes in several steroidogenic tissues, including the testis, ovary, adrenal cortex, and placenta. New evidence links the evolutionarily conserved Hh pathway to the steroidogenic organs, demonstrating how Hh signaling can influence their development and homeostasis and can act in concert with steroids to mediate physiological functions. In this review, we highlight the role of the components of the Hh signaling pathway in steroidogenesis of endocrine tissues.
-
-
-
Hypothalamic Inflammation in the Control of Metabolic Function
Vol. 77 (2015), pp. 131–160More LessDiet-induced obesity leads to devastating and common chronic diseases, fueling ongoing interest in determining new mechanisms underlying both obesity and its consequences. It is now well known that chronic overnutrition produces a unique form of inflammation in peripheral insulin target tissues, and efforts to limit this inflammation have met with some success in preserving insulin sensitivity in obese individuals. Recently, the activation of inflammatory pathways by dietary excess has also been observed among cells located in the mediobasal hypothalamus, a brain area that exerts central control over peripheral glucose, fat, and energy metabolism. Here we review progress in the field of diet-induced hypothalamic inflammation, drawing key distinctions between metabolic inflammation in the hypothalamus and that occurring in peripheral tissues. We focus on specific stimuli of the inflammatory response, the roles of individual hypothalamic cell types, and the links between hypothalamic inflammation and metabolic function under normal and pathophysiological circumstances. Finally, we explore the concept of controlling hypothalamic inflammation to mitigate metabolic disease.
-
-
-
Regulation of Body Fat in Caenorhabditis elegans
Vol. 77 (2015), pp. 161–178More LessOver the past decade, studies conducted in Caenorhabditis elegans have helped to uncover the ancient and complex origins of body fat regulation. This review highlights the powerful combination of genetics, pharmacology, and biochemistry used to study energy balance and the regulation of cellular fat metabolism in C. elegans. The complete wiring diagram of the C. elegans nervous system has been exploited to understand how the sensory nervous system regulates body fat and how food perception is coupled with the production of energy via fat metabolism. As a model organism, C. elegans also offers a unique opportunity to discover neuroendocrine factors that mediate direct communication between the nervous system and the metabolic tissues. The coming years are expected to reveal a wealth of information on the neuroendocrine control of body fat in C. elegans.
-
-
-
Cellular Homeostasis and Repair in the Mammalian Liver
Vol. 77 (2015), pp. 179–200More LessThe mammalian liver is one of the most regenerative tissues in the body, capable of fully recovering mass and function after a variety of injuries. This factor alone makes the liver unusual among mammalian tissues, but even more atypical is the widely held notion that the method of repair depends on the manner of injury. Specifically, the liver is believed to regenerate via replication of existing cells under certain conditions and via differentiation from specialized cells—so-called facultative stem cells—under others. Nevertheless, despite the liver's dramatic and unique regenerative response, the cellular and molecular features of liver homeostasis and regeneration are only now starting to come into relief. This review provides an overview of normal liver function and development and focuses on the evidence for and against various models of liver homeostasis and regeneration.
-
-
-
Hippo Pathway Regulation of Gastrointestinal Tissues
Vol. 77 (2015), pp. 201–227More LessThe Hippo pathway plays a crucial role in regulating tissue homeostasis and organ size, and its deregulation is frequently observed in human cancer. Yap is the major effector of and is inhibited by the Hippo pathway. In mouse model studies, inducible Yap expression in multiple tissues results in organ overgrowth. In the liver, knockout of upstream Hippo pathway components or transgenic expression of Yap leads to liver enlargement and hepatocellular carcinoma. In the small intestine or colon, deletion of upstream Hippo pathway components also results in expansion of intestinal progenitor cells and eventual development of adenomas. Genetic deletion of Yap in the intestine does not change the intestinal structure, but Yap is essential for intestinal repair upon certain types of tissue injury. The function of the Hippo pathway has also been studied in other gastrointestinal tissues, including the pancreas and stomach. Here we provide a brief overview of the Hippo pathway and discuss the physiological and pathological functions of this tumor suppressor pathway in gastrointestinal tissues.
-
-
-
Regeneration and Repair of the Exocrine Pancreas
Vol. 77 (2015), pp. 229–249More LessPancreatitis is caused by inflammatory injury to the exocrine pancreas, from which both humans and animal models appear to recover via regeneration of digestive enzyme–producing acinar cells. This regenerative process involves transient phases of inflammation, metaplasia, and redifferentiation, driven by cell-cell interactions between acinar cells, leukocytes, and resident fibroblasts. The NFκB signaling pathway is a critical determinant of pancreatic inflammation and metaplasia, whereas a number of developmental signals and transcription factors are devoted to promoting acinar redifferentiation after injury. Imbalances between these proinflammatory and prodifferentiation pathways contribute to chronic pancreatitis, characterized by persistent inflammation, fibrosis, and acinar dedifferentiation. Loss of acinar cell differentiation also drives pancreatic cancer initiation, providing a mechanistic link between pancreatitis and cancer risk. Unraveling the molecular bases of exocrine regeneration may identify new therapeutic targets for treatment and prevention of both of these deadly diseases.
-
-
-
Homeostatic Control of Presynaptic Neurotransmitter Release
Vol. 77 (2015), pp. 251–270More LessIt is well established that the active properties of nerve and muscle cells are stabilized by homeostatic signaling systems. In organisms ranging from Drosophila to humans, neurons restore baseline function in the continued presence of destabilizing perturbations by rebalancing ion channel expression, modifying neurotransmitter receptor surface expression and trafficking, and modulating neurotransmitter release. This review focuses on the homeostatic modulation of presynaptic neurotransmitter release, termed presynaptic homeostasis. First, we highlight criteria that can be used to define a process as being under homeostatic control. Next, we review the remarkable conservation of presynaptic homeostasis at the Drosophila, mouse, and human neuromuscular junctions and emerging parallels at synaptic connections in the mammalian central nervous system. We then highlight recent progress identifying cellular and molecular mechanisms. We conclude by reviewing emerging parallels between the mechanisms of homeostatic signaling and genetic links to neurological disease.
-
-
-
Intrinsic and Extrinsic Mechanisms of Dendritic Morphogenesis
Vol. 77 (2015), pp. 271–300More LessThe complex, branched morphology of dendrites is a cardinal feature of neurons and has been used as a criterion for cell type identification since the beginning of neurobiology. Regulated dendritic outgrowth and branching during development form the basis of receptive fields for neurons and are essential for the wiring of the nervous system. The cellular and molecular mechanisms of dendritic morphogenesis have been an intensely studied area. In this review, we summarize the major experimental systems that have contributed to our understandings of dendritic development as well as the intrinsic and extrinsic mechanisms that instruct the neurons to form cell type–specific dendritic arbors.
-
-
-
Concurrent Activation of Multiple Vasoactive Signaling Pathways in Vasoconstriction Caused by Tubuloglomerular Feedback: A Quantitative Assessment*
Vol. 77 (2015), pp. 301–322More LessTubuloglomerular feedback (TGF) describes the negative relationship between (a) NaCl concentration at the macula densa and (b) glomerular filtration rate or glomerular capillary pressure. TGF-induced vasoconstriction of the afferent arteriole results from the enhanced effect of several vasoconstrictors with an effect size sequence of adenosine = 20-HETE > angiotensin II > thromboxane = superoxide > renal nerves > ATP. TGF-mediated vasoconstriction is limited by the simultaneous release of several vasodilators with an effect size sequence of nitric oxide > carbon monoxide = kinins > adenosine. The sum of the constrictor effects exceeds that of the dilator effects by the magnitude of the TGF response. The validity of the additive model used in this analysis can be tested by determining the effect of combined inhibition of some or all agents contributing to TGF. Multiple independent contributors to TGF are consistent with the variability of TGF and of the factors contributing to TGF resetting.
-
-
-
The Molecular Physiology of Uric Acid Homeostasis
Vol. 77 (2015), pp. 323–345More LessUric acid, generated from the metabolism of purines, has proven and emerging roles in human disease. Serum uric acid is determined by production and the net balance of reabsorption or secretion by the kidney and intestine. A detailed understanding of epithelial absorption and secretion of uric acid has recently emerged, aided in particular by the results of genome-wide association studies of hyperuricemia. Novel genetic and regulatory networks with effects on uric acid homeostasis have also emerged. These developments promise to lead to a new understanding of the various diseases associated with hyperuricemia and to novel, targeted therapies for hyperuricemia.
-
-
-
Physiological Roles of Acid-Base Sensors
Vol. 77 (2015), pp. 347–362More LessAcid-base homeostasis is essential for life. The macromolecules upon which living organisms depend are sensitive to pH changes, and physiological systems use the equilibrium between carbon dioxide, bicarbonate, and protons to buffer their pH. Biological processes and environmental insults are constantly challenging an organism's pH; therefore, to maintain a consistent and proper pH, organisms need sensors that measure pH and that elicit appropriate responses. Mammals use multiple sensors for measuring both intracellular and extracellular pH, and although some mammalian pH sensors directly measure protons, it has recently become apparent that many pH-sensing systems measure pH via bicarbonate-sensing soluble adenylyl cyclase.
-
-
-
The Role of Pendrin in Renal Physiology
Vol. 77 (2015), pp. 363–378More LessPendrin is a Na+-independent Cl−/HCO3− exchanger that localizes to type B and non-A, non-B intercalated cells, which are expressed within the aldosterone-sensitive region of the nephron, i.e., the distal convoluted tubule, the connecting tubule, and the cortical collecting duct. Type B cells mediate Cl− absorption and HCO3− secretion primarily through pendrin-mediated Cl−/HCO3− exchange. At least in some treatment models, pendrin acts in tandem with the Na+-dependent Cl−/HCO3− exchanger (NDCBE) encoded by Slc4a8 to mediate NaCl absorption. The pendrin-mediated Cl−/HCO3− exchange process is greatly upregulated in models of metabolic alkalosis, such as following aldosterone administration or dietary NaHCO3 loading. It is also upregulated by angiotensin II. In the absence of pendrin [Slc26a4 (−/−) or pendrin null mice], aldosterone-stimulated NaCl absorption is reduced, which lowers the blood pressure response to aldosterone and enhances the alkalosis that follows the administration of this steroid hormone. Pendrin modulates aldosterone-induced Na+ absorption by changing ENaC abundance and function through a kidney-specific mechanism that does not involve changes in the concentration of a circulating hormone. Instead, pendrin changes ENaC abundance and function at least in part by altering luminal HCO3− and ATP concentrations. Thus, aldosterone and angiotensin II also stimulate pendrin expression and function, which likely contributes to the pressor response of these hormones. This review summarizes the contribution of the Cl−/HCO3− exchanger pendrin in distal nephron function.
-
-
-
Cilia Dysfunction in Lung Disease
Vol. 77 (2015), pp. 379–406More LessA characteristic feature of the human airway epithelium is the presence of ciliated cells bearing motile cilia, specialized cell surface projections containing axonemes composed of microtubules and dynein arms, which provide ATP-driven motility. In the airways, cilia function in concert with airway mucus to mediate the critical function of mucociliary clearance, cleansing the airways of inhaled particles and pathogens. The prototypical disorder of respiratory cilia is primary ciliary dyskinesia, an inherited disorder that leads to impaired mucociliary clearance, to repeated chest infections, and to the progressive destruction of lung architecture. Numerous acquired lung diseases are also marked by abnormalities in both cilia structure and function. In this review we summarize current knowledge regarding airway ciliated cells and cilia, how they function to maintain a healthy epithelium, and how disorders of cilia structure and function contribute to inherited and acquired lung disease.
-
-
-
Dynamics of Lung Defense in Pneumonia: Resistance, Resilience, and Remodeling
Vol. 77 (2015), pp. 407–430More LessPneumonia is initiated by microbes in the lung, but physiological processes integrating responses across diverse cell types and organ systems dictate the outcome of respiratory infection. Resistance, or actions of the host to eradicate living microbes, in the lungs involves a combination of innate and adaptive immune responses triggered by air-space infection. Resilience, or the ability of the host tissues to withstand the physiologically damaging effects of microbial and immune activities, is equally complex, precisely regulated, and determinative. Both immune resistance and tissue resilience are dynamic and change throughout the lifetime, but we are only beginning to understand such remodeling and how it contributes to the incidence of severe pneumonias, which diminishes as childhood progresses and then increases again among the elderly. Here, we review the concepts of resistance, resilience, and remodeling as they apply to pneumonia, highlighting recent advances and current significant knowledge gaps.
-
Previous Volumes
-
Volume 87 (2025)
-
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)