Annu Rev Physiol 2018 Feb;80:413-429

Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA; email:

AAA+ proteolytic machines use energy from ATP hydrolysis to degrade damaged, misfolded, or unneeded proteins. Protein degradation occurs within a barrel-shaped self-compartmentalized peptidase. Before protein substrates can enter this peptidase, they must be unfolded and then translocated through the axial pore of an AAA+ ring hexamer. Read More

Annu Rev Physiol 2018 Feb;80:353-387

Laboratory of Applied Mechanobiology, Institute of Translational Medicine, Department for Health Sciences and Technology, ETH Zürich, CH-8093 Zürich, Switzerland; email:

Cells need to be anchored to extracellular matrix (ECM) to survive, yet the role of ECM in guiding developmental processes, tissue homeostasis, and aging has long been underestimated. How ECM orchestrates the deterioration of healthy to pathological tissues, including fibrosis and cancer, also remains poorly understood. Inquiring how alterations in ECM fiber tension might drive these processes is timely, as mechanobiology is a rapidly growing field, and many novel mechanisms behind the mechanical forces that can regulate protein, cell, and tissue functions have recently been deciphered. Read More

Annu Rev Physiol 2018 Feb;80:327-351

Department of Biological Sciences, Columbia University, New York, NY 10027, USA; email: ,

Single-molecule atomic force microscopy and magnetic tweezers experiments have demonstrated that titin immunoglobulin (Ig) domains are capable of folding against a pulling force, generating mechanical work that exceeds that produced by a myosin motor. We hypothesize that upon muscle activation, formation of actomyosin cross bridges reduces the force on titin, causing entropic recoil of the titin polymer and triggering the folding of the titin Ig domains. In the physiological force range of 4-15 pN under which titin operates in muscle, the folding contraction of a single Ig domain can generate 200% of the work of entropic recoil and occurs at forces that exceed the maximum stalling force of single myosin motors. Read More

Annu Rev Physiol 2018 Feb 1;80:159-188. Epub 2017 Dec 1.

Department of Neuroscience, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA; email:

Synapses, the fundamental unit in neuronal circuits, are critical for learning and memory, perception, thinking, and reaction. The neuromuscular junction (NMJ) is a synapse formed between motoneurons and skeletal muscle fibers that is covered by Schwann cells (SCs). It is essential for controlling muscle contraction. Read More

Annu Rev Physiol 2018 Feb 1;80:71-93. Epub 2017 Dec 1.

Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia; email: , ,

Bacteria represent one of the most evolutionarily successful groups of organisms to inhabit Earth. Their world is awash with mechanical cues, probably the most ancient form of which are osmotic forces. As a result, they have developed highly robust mechanosensors in the form of bacterial mechanosensitive (MS) channels. Read More

Annu Rev Physiol 2018 Feb 20;80:143-157. Epub 2017 Nov 20.

Weill Institute for Neurosciences, University of California, San Francisco, California 94143; email:

Astrocytes are an abundant and evolutionarily conserved central nervous system cell type. Despite decades of evidence that astrocytes are integral to neural circuit function, it seems as though astrocytic and neuronal biology continue to advance in parallel to each other, to the detriment of both. Recent advances in molecular biology and optical imaging are being applied to astrocytes in new and exciting ways but without fully considering their unique biology. Read More

Annu Rev Physiol 2018 Feb 20;80:243-262. Epub 2017 Nov 20.

Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; email:

Research in the last two decades has identified many synaptic organizers in the central nervous system that directly regulate the assembly of pre- and/or postsynaptic molecules, such as synaptic vesicles, active zone proteins, and neurotransmitter receptors. They are classified into secreted factors and cell adhesion molecules, such as neurexins and neuroligins. Certain secreted factors are termed extracellular scaffolding proteins (ESPs) because they are components of the synaptic extracellular matrix and serve as a scaffold at the synaptic cleft. Read More

Annu Rev Physiol 2018 Feb 16;80:283-307. Epub 2017 Nov 16.

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina 27710, USA; email:

The link between inappropriate salt retention in the kidney and hypertension is well recognized. However, growing evidence suggests that the immune system can play surprising roles in sodium homeostasis, such that the study of inflammatory cells and their secreted effectors has provided important insights into salt sensitivity. As part of the innate immune system, myeloid cells have diverse roles in blood pressure regulation, ranging from prohypertensive actions in the kidney, vasculature, and brain, to effects in the skin that attenuate blood pressure elevation. Read More

Annu Rev Physiol 2018 Feb 13;80:389-411. Epub 2017 Nov 13.

Institute of Physiology II, University of Münster, 48149 Münster, Germany; email:

The thin and thick filaments of muscle sarcomeres are interconnected by the giant protein titin, which is a scaffolding filament, signaling platform, and provider of passive tension and elasticity in myocytes. This review summarizes recent insight into the mechanisms behind how titin gene mutations cause hereditary cardiomyopathy and how titin protein is mechanically active in skeletal and cardiac myocytes. A main theme is the evolving role of titin as a modulator of contraction. Read More

Annu Rev Physiol 2018 Feb 10;80:95-116. Epub 2017 Nov 10.

Division of Endocrinology, Gerontology and Metabolism, Stanford University School of Medicine, Stanford, California 94305; email:

The scavenger receptor, class B type 1 (SR-B1), is a multiligand membrane receptor protein that functions as a physiologically relevant high-density lipoprotein (HDL) receptor whose primary role is to mediate selective uptake or influx of HDL-derived cholesteryl esters into cells and tissues. SR-B1 also facilitates the efflux of cholesterol from peripheral tissues, including macrophages, back to liver. As a regulator of plasma membrane cholesterol content, SR-B1 promotes the uptake of lipid soluble vitamins as well as viral entry into host cells. Read More

Annu Rev Physiol 2018 Feb 9;80:263-281. Epub 2017 Nov 9.

Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA; email:

Epithelial Na channels (ENaCs) are members of the ENaC/degenerin family of ion channels that evolved to respond to extracellular factors. In addition to being expressed in the distal aspects of the nephron, where ENaCs couple the absorption of filtered Na to K secretion, these channels are found in other epithelia as well as nonepithelial tissues. This review addresses mechanisms by which ENaC activity is regulated by extracellular factors, including proteases, Na, and shear stress. Read More

Annu Rev Physiol 2018 Feb 25;80:1-26. Epub 2017 Oct 25.

Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA; email:

Autophagy is an evolutionarily conserved mechanism by which cytoplasmic elements are degraded intracellularly. Autophagy has also emerged as a major regulator of cardiac homeostasis and function. Autophagy preserves cardiac structure and function under baseline conditions and is activated during stress, limiting damage under most conditions. Read More

Annu Rev Physiol 2018 Feb 25;80:309-326. Epub 2017 Oct 25.

Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA; email:

Tubulointerstitial fibrosis is a chronic and progressive process affecting kidneys during aging and in chronic kidney disease (CKD), regardless of cause. CKD and renal fibrosis affect half of adults above age 70 and 10% of the world's population. Although no targeted therapy yet exists to slow renal fibrosis, a number of important recent advances have clarified the cellular and molecular mechanisms underlying the disease. Read More

Annu Rev Physiol 2018 Feb 13;80:117-141. Epub 2017 Oct 13.

Translational Research Center for Gastrointestinal Disorders, KU Leuven, 3000 Leuven, Belgium; email:

The gastrointestinal tract represents the largest interface between the human body and the external environment. It must continuously monitor and discriminate between nutrients that need to be assimilated and harmful substances that need to be expelled. The different cells of the gut epithelium are therefore equipped with a subtle chemosensory system that communicates the sensory information to several effector systems involved in the regulation of appetite, immune responses, and gastrointestinal motility. Read More

Annu Rev Physiol 2018 Feb 13;80:49-70. Epub 2017 Oct 13.

Stanford University School of Medicine, Stanford, California 94305, USA; email:

The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic regeneration occurs physiologically in wound healing and tissue repair, pathological lymphangiogenesis has been implicated in a number of chronic diseases such as lymphedema, atherosclerosis, and cancer. Insight into the regulatory mechanisms of lymphangiogenesis and the manner in which uncontrolled inflammation promotes lymphatic dysfunction is urgently needed to guide the development of novel therapeutics: These would be designed to reverse lymphatic dysfunction, either primary or acquired. Read More

Annu Rev Physiol 2018 Feb 27;80:189-217. Epub 2017 Sep 27.

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA; email:

The exteroceptive somatosensory system is important for reflexive and adaptive behaviors and for the dynamic control of movement in response to external stimuli. This review outlines recent efforts using genetic approaches in the mouse to map the spinal cord circuits that transmit and gate the cutaneous somatosensory modalities of touch, pain, and itch. Recent studies have revealed an underlying modular architecture in which nociceptive, pruritic, and innocuous stimuli are processed by distinct molecularly defined interneuron cell types. Read More

Annu Rev Physiol 2018 Feb 22;80:219-241. Epub 2017 Sep 22.

Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97239, USA; email:

In recent years, the population of neurons in the ventral tegmental area (VTA) and substantia nigra (SN) has been examined at multiple levels. The results indicate that the projections, neurochemistry, and receptor and ion channel expression in this cell population vary widely. This review centers on the intrinsic properties and synaptic regulation that control the activity of dopamine neurons. Read More

Annu Rev Physiol 2018 02 20;80:27-48. Epub 2017 Sep 20.

Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; email:

Aging, the main risk factor for cardiovascular disease (CVD), is becoming progressively more prevalent in our societies. A better understanding of how aging promotes CVD is therefore urgently needed to develop new strategies to reduce disease burden. Atherosclerosis and heart failure contribute significantly to age-associated CVD-related morbimortality. Read More

Annu Rev Physiol 2017 Feb;79:209-236

Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520; email:

The hypothalamus is an evolutionarily conserved brain structure that regulates an organism's basic functions, such as homeostasis and reproduction. Several hypothalamic nuclei and neuronal circuits have been the focus of many studies seeking to understand their role in regulating these basic functions. Within the hypothalamic neuronal populations, the arcuate melanocortin system plays a major role in controlling homeostatic functions. Read More

Annu Rev Physiol 2017 Feb;79:291-312

Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205; email:

The lack of accessibility to normal and diseased human intestine and the inability to separate the different functional compartments of the intestine even when tissue could be obtained have held back the understanding of human intestinal physiology. Clevers and his associates identified intestinal stem cells and established conditions to grow "mini-intestines" ex vivo in differentiated and undifferentiated conditions. This pioneering work has made a new model of the human intestine available and has begun making contributions to the understanding of human intestinal transport in normal physiologic conditions and the pathophysiology of intestinal diseases. Read More

Annu Rev Physiol 2017 Feb;79:449-469

Section of Nephrology, Department of Internal Medicine, Yale University, New Haven, Connecticut 06520; email:

Acute kidney injury (AKI) is a growing global health concern, yet no treatment is currently available to prevent it or to promote kidney repair after injury. Animal models demonstrate that the macrophage is a major contributor to the inflammatory response to AKI. Emerging data from human biopsies also corroborate the presence of macrophages in AKI and their persistence in progressive chronic kidney disease. Read More

Annu Rev Physiol 2017 Feb;79:471-494

Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10065; email:

Inflammasomes are key inflammatory signaling platforms that detect microbial substances, sterile environmental insults, and molecules derived from host cells. Activation of the inflammasome promotes caspase-1-mediated secretion of proinflammatory cytokines interleukin (IL)-1β and IL-18 and pyroptosis. Recent developments in this field demonstrate the crucial role of the inflammasome in a wide range of disease models. Read More

Annu Rev Physiol 2017 Feb;79:261-289

Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut 06510; email:

Active iodide (I) transport in both the thyroid and some extrathyroidal tissues is mediated by the Na/I symporter (NIS). In the thyroid, NIS-mediated I uptake plays a pivotal role in thyroid hormone (TH) biosynthesis. THs are key during embryonic and postembryonic development and critical for cell metabolism at all stages of life. Read More

Annu Rev Physiol 2017 Feb;79:335-356

Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan 48109; email:

The tongue is an elaborate complex of heterogeneous tissues with taste organs of diverse embryonic origins. The lingual taste organs are papillae, composed of an epithelium that includes specialized taste buds, the basal lamina, and a lamina propria core with matrix molecules, fibroblasts, nerves, and vessels. Because taste organs are dynamic in cell biology and sensory function, homeostasis requires tight regulation in specific compartments or niches. Read More

Annu Rev Physiol 2017 Feb 15;79:357-380. Epub 2016 Dec 15.

Department of Molecular and Cellular Physiology, University of Cincinnati, Cincinnati, Ohio 45267; email:

Trefoil factor (TFF) peptides, with a 40-amino acid motif and including six conserved cysteine residues that form intramolecular disulfide bonds, are a family of mucin-associated secretory molecules mediating many physiological roles that maintain and restore gastrointestinal (GI) mucosal homeostasis. TFF peptides play important roles in response to GI mucosal injury and inflammation. In response to acute GI mucosal injury, TFF peptides accelerate cell migration to seal the damaged area from luminal contents, whereas chronic inflammation leads to increased TFF expression to prevent further progression of disease. Read More

Annu Rev Physiol 2017 Feb 15;79:43-66. Epub 2016 Dec 15.

Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.

Angiogenesis has traditionally been viewed from the perspective of how endothelial cells (ECs) coordinate migration and proliferation in response to growth factor activation to form new vessel branches. However, ECs must also coordinate their metabolism and adapt metabolic fluxes to the rising energy and biomass demands of branching vessels. Recent studies have highlighted the importance of such metabolic regulation in the endothelium and uncovered core metabolic pathways and mechanisms of regulation that drive the angiogenic process. Read More

Annu Rev Physiol 2017 Feb 7;79:495-515. Epub 2016 Dec 7.

Departments of Anesthesiology and Pathology, Duke University School of Medicine, Durham, North Carolina 27710; email:

Remarkable new roles for mitochondria in calcium handling, apoptosis, heme turnover, inflammation, and oxygen and nutrient sensing have been discovered for organelles that were once thought to be simple energy converters. Although deficits in mitochondrial function are often associated with energy failure and apoptosis, working cells maintain a mitochondrial reserve that affords the organelles distinct homeostatic sensing and regulatory abilities in lung cells. As primary intracellular sources of oxidants, mitochondria serve as critical monitors and modulators of vital oxidation-reduction processes, including mitochondrial biogenesis, mitophagy, inflammasome activation, cell proliferation, and prevention of fibrosis. Read More

Annu Rev Physiol 2017 Feb 7;79:619-643. Epub 2016 Dec 7.

Cellular Neurosciences, Max Delbrück Centre for Molecular Medicine in the Helmholtz Association, Berlin 13092, Germany; email:

As the immune-competent cells of the brain, microglia play an increasingly important role in maintaining normal brain function. They invade the brain early in development, transform into a highly ramified phenotype, and constantly screen their environment. Microglia are activated by any type of pathologic event or change in brain homeostasis. Read More

Annu Rev Physiol 2017 Feb 7;79:567-592. Epub 2016 Dec 7.

Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, Maryland 20742; email:

In recent years, researchers have devoted much attention to the diverse roles of macrophages and their contributions to tissue development, wound healing, and angiogenesis. What should not be lost in the discussions regarding the diverse biology of these cells is that when perturbed, macrophages are the primary contributors to potentially pathological inflammatory processes. Macrophages stand poised to rapidly produce large amounts of inflammatory cytokines in response to danger signals. Read More

Annu Rev Physiol 2017 Feb 7;79:593-617. Epub 2016 Dec 7.

Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892; email: ,

Macrophages regulate tissue regeneration following injury. They can worsen tissue injury by producing reactive oxygen species and other toxic mediators that disrupt cell metabolism, induce apoptosis, and exacerbate ischemic injury. However, they also produce a variety of growth factors, such as IGF-1, VEGF-α, TGF-β, and Wnt proteins that regulate epithelial and endothelial cell proliferation, myofibroblast activation, stem and tissue progenitor cell differentiation, and angiogenesis. Read More

Annu Rev Physiol 2017 Feb 9;79:517-539. Epub 2016 Dec 9.

National Heart and Lung Institute, Imperial College, London SW3 6LY, United Kingdom; email:

Chronic obstructive pulmonary disease (COPD) is regarded as a disease of accelerated lung aging. This affliction shows all of the hallmarks of aging, including telomere shortening, cellular senescence, activation of PI3 kinase-mTOR signaling, impaired autophagy, mitochondrial dysfunction, stem cell exhaustion, epigenetic changes, abnormal microRNA profiles, immunosenescence, and a low-grade chronic inflammation (inflammaging). Many of these pathways are driven by chronic exogenous and endogenous oxidative stress. Read More

Annu Rev Physiol 2017 Feb 9;79:1-19. Epub 2016 Dec 9.

Department of Biology, Stanford University, Stanford, California 94305; email:

Coronary artery disease (CAD) is the number one cause of death worldwide and involves the accumulation of plaques within the artery wall that can occlude blood flow to the heart and cause myocardial infarction. The high mortality associated with CAD makes the development of medical interventions that repair and replace diseased arteries a high priority for the cardiovascular research community. Advancements in arterial regenerative medicine could benefit from a detailed understanding of coronary artery development during embryogenesis and of how these pathways might be reignited during disease. Read More

Annu Rev Physiol 2017 Feb 9;79:21-41. Epub 2016 Dec 9.

Departments of Genetics, Pediatrics, and Medicine (Cardiology), Wilf Cardiovascular Research Institute, Albert Einstein College of Medicine, Bronx, New York 10461; email:

Normal aortic valves are composed of valve endothelial cells (VECs) and valve interstitial cells (VICs). VICs are the major cell population and have distinct embryonic origins in the endocardium and cardiac neural crest cells. Cell signaling between the VECs and VICs plays critical roles in aortic valve morphogenesis. Read More

Annu Rev Physiol 2017 Feb 28;79:401-423. Epub 2016 Nov 28.

Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147; email:

The neural control of appetite is important for understanding motivated behavior as well as the present rising prevalence of obesity. Over the past several years, new tools for cell type-specific neuron activity monitoring and perturbation have enabled increasingly detailed analyses of the mechanisms underlying appetite-control systems. Three major neural circuits strongly and acutely influence appetite but with notably different characteristics. Read More

Annu Rev Physiol 2017 Feb 28;79:313-334. Epub 2016 Nov 28.

Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109; email:

Bariatric surgeries, such as Roux-en-Y gastric bypass and vertical sleeve gastrectomy, produce significant and durable weight loss in both humans and rodents. Recently, these surgical interventions have also been termed metabolic surgery because they result in profound metabolic improvements that often surpass the expected improvement due to body weight loss alone. In this review we focus on the weight-loss independent effects of bariatric surgery, which encompass energy expenditure and macronutrient preference, the luminal composition of the gut (i. Read More

Annu Rev Physiol 2017 Feb 14;79:237-260. Epub 2016 Nov 14.

Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut 06030; email: ,

Meiotic progression in mammalian preovulatory follicles is controlled by the granulosa cells around the oocyte. Cyclic GMP (cGMP) generated in the granulosa cells diffuses through gap junctions into the oocyte, maintaining meiotic prophase arrest. Luteinizing hormone then acts on receptors in outer granulosa cells to rapidly decrease cGMP. Read More

Annu Rev Physiol 2017 Feb 16;79:93-117. Epub 2016 Nov 16.

Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80303; email:

Fluorescent tools have revolutionized our ability to probe biological dynamics, particularly at the cellular level. Fluorescent sensors have been developed on several platforms, utilizing either small-molecule dyes or fluorescent proteins, to monitor proteins, RNA, DNA, small molecules, and even cellular properties, such as pH and membrane potential. We briefly summarize the impressive history of tool development for these various applications and then discuss the most recent noteworthy developments in more detail. Read More

Annu Rev Physiol 2017 Feb 16;79:119-143. Epub 2016 Nov 16.

Department of Cell Biology, Emory University School of Medicine, Atlanta, Georgia 30322; email:

Anoctamin (ANO)/TMEM16 proteins exhibit diverse functions in cells throughout the body and are implicated in several human diseases. Although the founding members ANO1 (TMEM16A) and ANO2 (TMEM16B) are Ca-activated Cl channels, most ANO paralogs are Ca-dependent phospholipid scramblases that serve as channels facilitating the movement (scrambling) of phospholipids between leaflets of the membrane bilayer. Phospholipid scrambling significantly alters the physical properties of the membrane and its landscape and has vast downstream signaling consequences. Read More

Annu Rev Physiol 2017 Feb 16;79:187-208. Epub 2016 Nov 16.

Department of Biology, York University, Toronto, Ontario M3J 1P3, Canada.

Cold tolerance is important in defining the distribution of insects. Here, we review the principal physiological mechanisms underlying homeostatic failure during cold exposure in this diverse group of ectotherms. When insects are cooled sufficiently, they suffer an initial loss of neuromuscular function (chill coma) that is caused by decreased membrane potential and reduced excitability of the neuromuscular system. Read More

Annu Rev Physiol 2017 Feb 13;79:381-399. Epub 2016 Oct 13.

Department of Neuroscience and Kavli Institute for Brain Science, Columbia University Medical Center, New York, NY 10032; email:

Perception of the environment requires differentiating between external sensory inputs and those that are self-generated. Some of the clearest insights into the neural mechanisms underlying this process have come from studies of the electrosensory systems of fish. Neurons at the first stage of electrosensory processing generate negative images of the electrosensory consequences of the animal's own behavior. Read More

Annu Rev Physiol 2017 Feb 21;79:541-566. Epub 2016 Oct 21.

Departments of Infectious Diseases and Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105; email:

Macrophage polarization refers to how macrophages have been activated at a given point in space and time. Polarization is not fixed, as macrophages are sufficiently plastic to integrate multiple signals, such as those from microbes, damaged tissues, and the normal tissue environment. Three broad pathways control polarization: epigenetic and cell survival pathways that prolong or shorten macrophage development and viability, the tissue microenvironment, and extrinsic factors, such as microbial products and cytokines released in inflammation. Read More

Annu Rev Physiol 2017 Feb 21;79:67-91. Epub 2016 Oct 21.

Vascular Biology Program, Department of Surgery, Harvard Medical School and Boston Children's Hospital, Boston, Massachusetts 02115; email: ,

Vertebrates are endowed with a closed circulatory system, the evolution of which required novel structural and regulatory changes. Furthermore, immune cell trafficking paradigms adapted to the barriers imposed by the closed circulatory system. How did such changes occur mechanistically? We propose that spatial compartmentalization of the lipid mediator sphingosine 1-phosphate (S1P) may be one such mechanism. Read More

Annu Rev Physiol 2017 Feb 28;79:425-448. Epub 2016 Oct 28.

Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261; email: ,

Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular ultrafiltrate to maintain essentially protein-free urine. Compromise of this pathway results in low molecular weight (LMW) proteinuria that can progress to end-stage kidney disease. This review describes our current understanding of the endocytic pathway and the multiligand receptors that mediate LMW protein uptake in PT cells, how these are regulated in response to physiologic cues, and the molecular basis of inherited diseases characterized by LMW proteinuria. Read More

Annu Rev Physiol 2017 Feb 28;79:167-186. Epub 2016 Oct 28.

Department of Biomedical and Neuromotor Sciences, Physiology Division, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; email:

Autonomic thermoregulation is a recently acquired function, as it appears for the first time in mammals and provides the brain with the ability to control energy expenditure. The importance of such control can easily be highlighted by the ability of a heterogeneous group of mammals to actively reduce metabolic rate and enter a condition of regulated hypometabolism known as torpor. The central neural circuits of thermoregulatory cold defense have been recently unraveled and could in theory be exploited to reduce energy expenditure in species that do not normally use torpor, inducing a state called synthetic torpor. Read More

Annu Rev Physiol 2017 Feb 28;79:145-166. Epub 2016 Oct 28.

Department of Biological Sciences, Northern Arizona University, Flagstaff, Arizona 86011-4185; email:

Although superthin filaments were inferred from early experiments on muscle, decades passed before their existence was accepted. Phylogenetic analyses suggest that titin, the largest known protein, first appeared in the common ancestor of chordates and nematodes and evolved rapidly via duplication. Twitchin and projectin evolved later by truncation. Read More

Annu Rev Physiol 2016 ;78:v-vi

Annu Rev Physiol 2016 ;78:437-61

Feinberg Cardiovascular Research Institute and Division of Nephrology and Hypertension, Northwestern University, Chicago, Illinois 60611; email: ,

The glomerulus is a highly specialized microvascular bed that filters blood to form primary urinary filtrate. It contains four cell types: fenestrated endothelial cells, specialized vascular support cells termed podocytes, perivascular mesangial cells, and parietal epithelial cells. Glomerular cell-cell communication is critical for the development and maintenance of the glomerular filtration barrier. Read More

Annu Rev Physiol 2016 ;78:367-89

Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, and Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico City 14080, Mexico; email:

The discovery of four genes responsible for pseudohypoaldosteronism type II, or familial hyperkalemic hypertension, which features arterial hypertension with hyperkalemia and metabolic acidosis, unmasked a complex multiprotein system that regulates electrolyte transport in the distal nephron. Two of these genes encode the serine-threonine kinases WNK1 and WNK4. The other two genes [kelch-like 3 (KLHL3) and cullin 3 (CUL3)] form a RING-type E3-ubiquitin ligase complex that modulates WNK1 and WNK4 abundance. Read More

Annu Rev Physiol 2016 ;78:351-65

Department of Cellular and Molecular Pharmacology and.

For more than 20 years, we have known that Ca(2+)/calmodulin-dependent protein kinase (CaMKII) activation is both necessary and sufficient for the induction of long-term potentiation (LTP). During this time, tremendous effort has been spent in attempting to understand how CaMKII activation gives rise to this phenomenon. Despite such efforts, there is much to be learned about the molecular mechanisms involved in LTP induction downstream of CaMKII activation. Read More

Annu Rev Physiol 2016 ;78:207-21

Division of Endocrinology, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan 48105; email:

Although it has been known for more than a century that the brain controls overall energy balance and adiposity by regulating feeding behavior and energy expenditure, the roles for individual brain regions and neuronal subtypes were not fully understood until recently. This area of research is active, and as such our understanding of the central regulation of energy balance is continually being refined as new details emerge. Much of what we now know stems from the discoveries of leptin and the hypothalamic melanocortin system. Read More