A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness, and lifestyle, affecting in equal measure women and men, athletes and couch potatoes, spinach eaters and fast food enthusiasts. Importantly, the decline in mHR is the major determinant of the age-dependent decline in aerobic capacity

Cardiac fibrosis is a pathological condition that occurs after injury and during aging. Currently, there are limited means to effectively reduce or reverse fibrosis. Key to identifying methods for curbing excess deposition of extracellular matrix is a better understanding of the cardiac fibroblast, the cell responsible for collagen production. In recent years, the diversity and functions of these enigmatic

Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous

In the body, extracellular stimuli produce inositol 1,4,5-trisphosphate (IP3), an intracellular chemical signal that binds to the IP3 receptor (IP3R) to release calcium ions (Ca2+) from the endoplasmic reticulum. In the past 40 years, the wide-ranging functions mediated by IP3R and its genetic defects causing a variety of disorders have been unveiled. Recent cryo-electron microscopy and X-ray crystallography

Endocrine disrupting chemicals are common in our environment and act on hormone systems and signaling pathways to alter physiological homeostasis. Gestational exposure can disrupt developmental programs, permanently altering tissues with impacts lasting into adulthood. The brain is a critical target for developmental endocrine disruption, resulting in altered neuroendocrine control of hormonal signaling

Chronic kidney disease (CKD) is a global health epidemic that accelerates cardiovascular disease, increases risk of infection, and causes anemia and bone disease, among other complications that collectively increase risk of premature death. Alterations in calcium and phosphate homeostasis have long been considered nontraditional risk factors for many of the most morbid outcomes of CKD. The discovery

Although chronic obstructive pulmonary disease (COPD) risk is strongly influenced by cigarette smoking, genetic factors are also important determinants of COPD. In addition to Mendelian syndromes such as alpha-1 antitrypsin deficiency, many genomic regions that influence COPD susceptibility have been identified in genome-wide association studies. Similarly, multiple genomic regions associated with

People worldwide are living longer, and it is estimated that by 2050, the proportion of the world's population over 60 years of age will nearly double. Natural lung aging is associated with molecular and physiological changes that cause alterations in lung function, diminished pulmonary remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. As the aging

Osteocytes are an ancient cell, appearing in fossilized skeletal remains of early fish and dinosaurs. Despite its relative high abundance, even in the context of nonskeletal cells, the osteocyte is perhaps among the least studied cells in all of vertebrate biology. Osteocytes are cells embedded in bone, able to modify their surrounding extracellular matrix via specialized molecular remodeling mechanisms

Genetic variants in the APOL1 gene, found only in individuals of recent African ancestry, greatly increase risk of multiple types of kidney disease. These APOL1 kidney risk alleles are a rare example of genetic variants that are common but also have a powerful effect on disease susceptibility. These alleles rose to high frequency in sub-Saharan Africa because they conferred protection against pathogenic

The skeleton harbors an array of lineage cells that have an essential role in whole body homeostasis. Adipocytes start the colonization of marrow space early in postnatal life, expanding progressively and influencing other components of the bone marrow through paracrine signaling. In this unique, closed, and hypoxic environment close to the endosteal surface and adjacent to the microvascular space

Studies of the physiology and biomechanics of small ( approximately 1 cm) organisms are often limited by the inability to see inside the animal during a behavior or process of interest and by a lack of three-dimensional morphology at the submillimeter scale. These constraints can be overcome by an imaging probe that has sensitivity to soft tissue, the ability to penetrate opaque surfaces, and high

Steroids play an important role in the regulation of normal physiology and the treatment of disease. Steroid receptors have classically been described as ligand-activated transcription factors mediating long-term genomic effects in hormonally regulated tissues. It is now clear that steroids also mediate rapid signaling events traditionally associated with growth factor receptors and G protein-coupled

Neurons that produce gonadotropin-releasing hormone (GnRH) reside in the basal forebrain and drive reproductive function in mammals. Understanding the circuitry that regulates GnRH neurons is fundamental to comprehending the neuroendocrine control of puberty and reproduction in the adult. This review focuses on a family of neuropeptides encoded by the Kiss1 gene, the kisspeptins, and their cognate

Insulin-like signaling is critical for nutrient homeostasis, growth and survival. However, work with lower metazoans-Caenorhabditis elegans and Drosophila-shows that reduced insulin-like signaling extends life span. In addition, reduced insulin signaling in higher animals-rodents and humans-causes glucose intolerance and hyperinsulinemia that progresses to diabetes and shortens the life span of affected

Calcium (Ca) is a universal intracellular second messenger. In muscle, Ca is best known for its role in contractile activation. However, in recent years the critical role of Ca in other myocyte processes has become increasingly clear. This review focuses on Ca signaling in cardiac myocytes as pertaining to electrophysiology (including action potentials and arrhythmias), excitation-contraction coupling

The incidences of both obesity and type 2 diabetes mellitus are rising at epidemic proportions. Despite this, the balance between caloric intake and expenditure is tremendously accurate under most circumstances. Growing evidence suggests that nutrient and hormonal signals converge and directly act on brain centers, leading to changes in fuel metabolism and, thus, stable body weight over time. Growing

Major advances in understanding regulated mucin secretion from airway goblet cells have been made in the past decade in the areas of pharmacology and basic cell biology. For instance, it is now appreciated that nucleotide agonists acting locally through P2Y purinoceptors on apical membranes of surface goblet cells provide the major regulatory system for mucin secretion. Similarly, Clara cells, the

Cyclooxygenase-derived prostanoids exert complex and diverse functions within the kidney. The biological effect of each prostanoid is controlled at multiple levels, including (a) enzymatic reactions catalyzed sequentially by cyclooxygenase and prostanoid synthase for the synthesis of bioactive prostanoid and (b) the interaction with its receptors that mediate its functions. Cyclooxygenase-derived prostanoids

Sperm are attracted by chemical factors that are released by the egg-a process called chemotaxis. Most of our knowledge on sperm chemotaxis originates from the study of marine invertebrates. In recent years, the main features of the chemotactic signaling pathway and the swimming behavior evoked by chemoattractants have been elucidated in sea urchins. In contrast, our understanding of mammalian sperm

The concept of a regulatory link between the gastrointestinal tract and kidneys is not new. The idea that dietary intake and composition can affect renal function is perhaps self-evident, but defining this relationship, especially in terms of sensors and effectors, is proving more difficult. That the gastrointestinal tract can exert some control over renal function was strengthened by the early observation

Mucins are important components that exert a variety of functions in cell-cell interaction, epidermal growth factor receptor signaling, and airways protection. In the conducting airways of the lungs, mucins are the major contributor to the viscoelastic property of mucous secretion, which is the major barrier to trapping inhaled microbial organism, particulates, and oxidative pollutants. The homeostasis

Mutations in the serine-threonine kinases WNK1 and WNK4 cause a Mendelian disease featuring hypertension and hyperkalemia. In vitro and in vivo studies have revealed that these proteins are molecular switches that have discrete functional states that impart different effects on downstream ion channels, transporters, and the paracellular pathway. These effects enable the distal nephron to allow either

The discovery of aquaporin water channels by Agre and coworkers answered a long-standing biophysical question of how the majority of water crosses biological membranes. The identification and study of aquaporins have provided insight, at the molecular level, into the fundamental physiology of water balance regulation and the pathophysiology of water balance disorders. In addition to the originally

The adipose tissue-derived hormone leptin acts via its receptor (LRb) in the brain to regulate energy balance and neuroendocrine function. LRb signaling via STAT3 and a number of other pathways is required for the totality of leptin action. The failure of elevated leptin levels to suppress feeding and mediate weight loss in common forms of obesity defines a state of so-called leptin resistance. A number

The increasing prevalence of obesity worldwide has imparted renewed impetus to the study of the mechanisms of appetite regulation. Digestion and nutrient absorption take place in the gastrointestinal (GI) tract, whereas food intake is controlled by neuronal circuits in the central nervous system. The need for gut-brain cross talk is therefore clear. It is now recognized that hormones released into

Since the time of Muybridge and Marey in the last half of the nineteenth century, studies of animal movement have relied on some form of high-speed or stop-action imaging to permit analysis of appendage and body motion. In the past ten years, the advent of megapixel-resolution high-speed digital imaging with maximal framing rates of 250 to 100,000 images per second has allowed new views of musculoskeletal

The airways mucus gel performs a critical function in defending the respiratory tract against pathogenic and environmental challenges. In normal physiology, the secreted mucins, in particular the polymeric mucins MUC5AC and MUC5B, provide the organizing framework of the airways mucus gel and are major contributors to its rheological properties. However, overproduction of mucins is an important factor

Cytosolic Ca2+ signals are crucial for the control of fluid and enzyme secretion from exocrine glands. The highly polarized exocrine acinar cells have evolved sophisticated and complex Ca2+ signaling mechanisms that exercise precise control of the secretory events occurring across the apical plasma membrane bordering the gland lumen. Ca2+ stores in the endoplasmic reticulum, the secretory granules

Ca2+ is essential for numerous physiological functions in our bodies. Therefore, its homeostasis is finely maintained through the coordination of intestinal absorption, renal reabsorption, and bone resorption. The Ca2+-selective epithelial channels TRPV5 and TRPV6 have been identified, and their physiological roles have been revealed: TRPV5 is important in final renal Ca2+ reabsorption, and TRPV6 has

Low oxygen (O2) levels are a naturally occurring feature of embryonic development, adult physiology, and diseases such as those of the cardiovascular system. Although many responses to O2 deprivation are mediated by hypoxia-inducible factors (HIFs), researchers are finding a growing number of HIF-independent pathways that promote O2 conformance and hypoxia tolerance. Here, we describe HIF-independent

Cell surface mucins are large transmembrane glycoproteins involved in diverse functions ranging from shielding the airway epithelium against pathogenic infection to regulating cellular signaling and transcription. Although hampered by the relatively recent characterization of cell surface mucins and the difficulties inherent in working with molecules of their size, numerous studies have placed the

Bcl-2 family members are important regulators of cell survival and cell death. Researchers have focused mainly on mitochondria, where both proapoptotic and antiapoptotic family members function to regulate the release of cytochrome c and other mediators of apoptosis. However, as reviewed here, Bcl-2 family members also operate on another front, the endoplasmic reticulum (ER), to both positively and

This article mainly presents, in sequential panels of time, an overview of my professional involvements and laboratory experiences. I became smitten with red blood cells early on, and this passion remains with me to this day. I highlight certain studies, together with those who performed the work, recognizing that it was necessary to limit the details and the topics chosen for discussion. I am uncertain

Upon their discovery, beta-arrestins 1 and 2 were named for their capacity to sterically hinder the G protein coupling of agonist-activated seven-transmembrane receptors, ultimately resulting in receptor desensitization. Surprisingly, recent evidence shows that beta-arrestins can also function to activate signaling cascades independently of G protein activation. By serving as multiprotein scaffolds

Heterotrimeric G protein-coupled receptors (GPCRs) are found on the surface of all cells of multicellular organisms and are major mediators of intercellular communication. More than 800 distinct GPCRs are present in the human genome, and individual receptor subtypes respond to hormones, neurotransmitters, chemokines, odorants, or tastants. GPCRs represent the most widely targeted pharmacological protein

Small lipophilic molecules such as steroidal hormones, retinoids, and free fatty acids control many of the reproductive, developmental, and metabolic processes in eukaryotes. The mediators of these effects are nuclear receptor proteins, ligand-activated transcription factors capable of regulating the expression of complex gene networks. This review addresses the structure and structural properties

This review investigates some key aspects of transport mechanisms and recent advances in our understanding of this ubiquitous cellular process. The prevailing model of cotransport is the alternating access model, which suggests that large conformational changes in the transporter protein accompany cotransport. This model rests on decades of research and has received substantial support because many

In the vertebrate inner retina, the second stage of the visual system, different components of the visual scene are transformed, discarded, or selected before visual information is transmitted through the optic nerve. This review discusses the connections between higher-level functions of visual processing, mathematical descriptions of the neural code, inner retinal circuitry, and visual computations

Cilia, hair-like structures extending from the cell membrane, perform diverse biological functions. Primary (genetic) defects in the structure and function of sensory and motile cilia result in multiple ciliopathies. The most prominent genetic abnormality involving motile cilia (and the respiratory tract) is primary ciliary dyskinesia (PCD). PCD is a rare, usually autosomal recessive, genetically heterogeneous

In work spanning more than a century, mitochondria have been recognized for their multifunctional roles in metabolism, energy transduction, ion transport, inheritance, signaling, and cell death. Foremost among these tasks is the continuous production of ATP through oxidative phosphorylation, which requires a large electrochemical driving force for protons across the mitochondrial inner membrane. This

Many animal models are available to investigate the pathogenesis of pancreatitis, an inflammatory disorder of the pancreas. However, the secretagogue hyperstimulation model of pancreatitis is the most commonly used. Animals infused with high doses of cholecystokinin (CCK) exhibit hyperamylasemia, pancreatic edema, and acinar cell injury, which closely mimic pancreatitis in humans. Intra-acinar zymogen

A blink in history's eye has brought us an understanding of electricity, and with it a revolution in human life. From the frog leg twitch experiments of Galvani and the batteries of Volta, we have progressed to telegraphs, motors, telephones, computers, and the Internet. In the same period, the ubiquitous role of electricity in animal and plant life has become clear. A great milestone in this journey

All mammals and birds must develop effective strategies to cope with reduced oxygen availability. These animals achieve tolerance to acute and chronic hypoxia by (a) reductions in metabolism, (b) the prevention of cellular injury, and (c) the maintenance of functional integrity. Failure to meet any one of these tasks is detrimental. Birds and mammals accomplish this triple task through a highly coordinated

The ability of fishes, amphibians, and reptiles to survive extremes of oxygen availability derives from a core triad of adaptations: profound metabolic suppression, tolerance of ionic and pH disturbances, and mechanisms for avoiding free-radical injury during reoxygenation. For long-term anoxic survival, enhanced storage of glycogen in critical tissues is also necessary. The diversity of body morphologies

Steroid hormone receptors (SRs) are ligand-activated transcription factors and sensors for growth factor-initiated signaling pathways in hormonally regulated tissues, such as the breast or prostate. Recent discoveries suggest that several protein kinases are rapidly activated in response to steroid hormone binding to cytoplasmic SRs. Induction of rapid signaling upon SR ligand binding ensures that

To ensure that extracellular stimuli are translated into intracellular signals of appropriate magnitude and specificity, most signaling cascades are tightly regulated. One of the major mechanisms involved in the regulation of G protein-coupled receptors (GPCRs) involves their endocytic trafficking. GPCR endocytic trafficking entails the targeting of receptors to discrete endocytic sites at the plasma

Iron is needed by all mammalian cells but is toxic in excess. Specialized transport mechanisms conduct iron across cellular membranes. These are regulated to ensure homeostasis both systemically in living organisms and within individual cells. Over the past decade, major advances have been made in identifying and characterizing the proteins involved in the transport, handling, and homeostatic regulation

Cilia are membrane-bounded, centriole-derived projections from the cell surface that contain a microtubule cytoskeleton, the ciliary axoneme, surrounded by a ciliary membrane. Axonemes in multiciliated cells of mammalian epithelia are 9 + 2, possess dynein arms, and are motile. In contrast, single nonmotile 9 + 0 primary cilia are found on epithelial cells, such as those of the kidney tubule, but also

Studies of the stomatogastric nervous systems of lobsters and crabs have led to numerous insights into the cellular and circuit mechanisms that generate rhythmic motor patterns. The small number of easily identifiable neurons allowed the establishment of connectivity diagrams among the neurons of the stomatogastric ganglion. We now know that (a) neuromodulatory substances reconfigure circuit dynamics

Over the past decade there has been considerable progress in elucidating the signaling pathways involved in cardioprotection. Considerable recent data suggest that many of these signaling pathways converge on the mitochondria, where such pathways alter the activity of key mitochondrial proteins, leading to reduced apoptosis and necrosis. Inhibition of the mitochondrial permeability transition pore

Sulfate is essential for normal cellular function. The kidney plays a major role in sulfate homeostasis. Sulfate is freely filtered and then undergoes net reabsorption in the proximal tubule. The apical membrane Na(+)/sulfate cotransporter NaS1 (SLC13A1) has a major role in mediating proximal tubule sulfate reabsorption, as demonstrated by the findings of hyposulfatemia and hypersulfaturia in Nas1-null

Receptor tyrosine kinases (RTKs) are a unique family of cell surface receptors, each containing a common intracellular domain that has tyrosine kinase activity. However, RTKs share many signaling molecules with another unique family of cell surface receptors, the seven-transmembrane receptors (7TMRs), and these receptor families can activate similar signaling cascades. In this review of RTK signaling

The identification of defective structures in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in patients with sitosterolemia suggests that these two proteins are an apical sterol export pump promoting active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. The newly identified Niemann-Pick C1-like 1 (NPC1L1) protein is also expressed

Acid-base homeostasis to a great extent relies on renal ammonia metabolism. In the past several years, seminal studies have generated important new insights into the mechanisms of renal ammonia transport. In particular, the theory that ammonia transport occurs almost exclusively through nonionic NH(3) diffusion and NH(4)(+) trapping has given way to a model postulating that a variety of proteins specifically