Annual Review of Physiology - Volume 75, 2013

In the second century ad, Galen of Pergamon was the first to describe the anatomical connection between the hypothalamus and the pituitary gland. In the 1800s, von Luska, Cajal, and others showed that this connecting structure, or stalk, contains nerve fibers as well as a plexus of capillary vessels. Such observations raised long-standing questions as to the functional nature of these connections and their relationship to neural and/or humoral communication between these two endocrine organs.

Hypothalamic nerve fibers projecting to the posterior pituitary were later shown to account for the release of vasopressin and oxytocin from vesicle-rich terminals within this lobe. Up until the mid-1900s, however, it remained unclear as to how the hypothalamus controls the release of corticotropin, thyrotropin, growth hormone, and other key endocrine factors from the anterior lobe. Evidence for direct neural control was lacking, and in the 1940s the British physiologist Geoffrey Harris proposed that the hypothalamus exerts control over the anterior lobe through a humoral mechanism in which blood-borne releasing factors are delivered to the pituitary through capillaries of the interconnecting stalk (the so-called hypothalamo-hypophysial portal system), inducing cells in the anterior lobe to secrete their hormones. This model was not without controversy, and skeptics would not be satisfied until the mythical hypothalamic releasing factors had been biochemically and functionally identified. In 1977, Roger Guillemin and Andrew Schally shared the Nobel Prize in Medicine and Physiology for accomplishing this daunting and far-reaching goal. In doing so, they established the field of neuroendocrinology.

In this Perspective, Dr. Guillemin, Distinguished Professor at the Salk Institute, recalls events that diverted him from a career as a country doctor in his native France to one of scientific research, first in Canada and then in the United States and France. The story of the releasing factors is legendary, not only for its scientific import, but also for the great technical challenges that beset these efforts when the advantages of protein microsequencing, molecular cloning, and other such powerful techniques were not yet available. Rather, a scale and persistence of experimentation almost unthinkable (and likely unfundable) by today's standards proved successful. Consequently, key steps in hypothalamic-pituitary signaling were elucidated, and new pharmacological strategies for treating endocrine disorders, including those affecting stature and reproduction, were realized.

Following on a recent Annual Review of Physiology (ARP) advent, this Perspective takes the form of an oral history that can be read here in transcript form and viewed online. Dr. Guillemin was interviewed on August 7, 2012, at his ranch in the beautiful hills of Truchas, New Mexico (see Figure 1), by Dr. Greg Lemke, Françoise Gilot–Salk Chair at the Salk Institute. We are most grateful to Roger Guillemin and to his wife, Lucienne, for opening their home to ARP for this interview, as well as to Greg Lemke for guiding this lively and fascinating conversation.

The vascular adventitia acts as a biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. It is the most complex compartment of the vessel wall and is composed of a variety of cells, including fibroblasts, immunomodulatory cells (dendritic cells and macrophages), progenitor cells, vasa vasorum endothelial cells and pericytes, and adrenergic nerves. In response to vascular stress or injury, resident adventitial cells are often the first to be activated and reprogrammed to influence the tone and structure of the vessel wall; to initiate and perpetuate chronic vascular inflammation; and to stimulate expansion of the vasa vasorum, which can act as a conduit for continued inflammatory and progenitor cell delivery to the vessel wall. This review presents the current evidence demonstrating that the adventitia acts as a key regulator of vascular wall function and structure from the outside in.

The endoplasmic reticulum (ER) is a multifunctional intracellular organelle, a component of the cellular reticular network that allows cells to adjust to a wide variety of conditions. The cardiomyocyte reticular network is the ideal location of sensors for both intrinsic and extrinsic factors that disrupt energy and/or nutrient homeostasis and lead to ER stress, a disturbance in ER function. ER stress has been linked to both physiological and pathological states in the cardiovascular system; such states include myocardial infarction, oxygen starvation (hypoxia) and fuel starvation, ischemia, pressure overload, dilated cardiomyopathy, hypertrophy, and heart failure. The ER stress coping response (e.g., the unfolded protein response) is composed of discrete pathways that are controlled by a collection of common regulatory components that may function as a single entity involved in reacting to ER stress. These corrective strategies allow the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. Therefore, the identities of the ER stress corrective strategies are important targets for the development of therapeutic approaches for cardiovascular and other acquired disorders.

In 1993, lin-4 was discovered as a critical modulator of temporal development in Caenorhabditis elegans and, most notably, as the first in the class of small, single-stranded noncoding RNAs now defined as microRNAs (miRNAs). Another eight years elapsed before miRNA expression was detected in mammalian cells. Since then, explosive advancements in the field of miRNA biology have elucidated the basic mechanism of miRNA biogenesis, regulation, and gene-regulatory function. The discovery of this new class of small RNAs has augmented the complexity of gene-regulatory programs as well as the understanding of developmental and pathological processes in the cardiovascular system. Indeed, the contributions of miRNAs in cardiovascular development and function have been widely explored, revealing the extensive role of these small regulatory RNAs in cardiovascular physiology.

The eukaryote's mitochondrial network is perhaps the cell's most sophisticated and dynamic responsive sensing system. Integrating metabolic, oxygen, or danger signals with inputs from other organelles, as well as local and systemic signals, mitochondria have a profound impact on vascular function in both health and disease. This review highlights recently discovered aspects of mitochondrial function (oxygen sensing, inflammation, autophagy, and apoptosis) and discusses their role in diseases of both systemic and pulmonary vessels. We also emphasize the role of mitochondria as therapeutic targets for vascular disease. We highlight the intriguing similarities of mitochondria-driven molecular mechanisms in terms of both pathogenesis and therapies in very diverse diseases, such as atherosclerosis, pulmonary hypertension, and cancer, to support the foundation of a new field in medicine: mitochondrial medicine.

Phospholipase C (PLC) converts phosphatidylinositol 4,5-bisphosphate (PIP2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). DAG and IP3 each control diverse cellular processes and are also substrates for synthesis of other important signaling molecules. PLC is thus central to many important interlocking regulatory networks. Mammals express six families of PLCs, each with both unique and overlapping controls over expression and subcellular distribution. Each PLC also responds acutely to its own spectrum of activators that includes heterotrimeric G protein subunits, protein tyrosine kinases, small G proteins, Ca²⁺, and phospholipids. Mammalian PLCs are autoinhibited by a region in the catalytic TIM barrel domain that is the target of much of their acute regulation. In combination, the PLCs act as a signaling nexus that integrates numerous signaling inputs, critically governs PIP2 levels, and regulates production of important second messengers to determine cell behavior over the millisecond to hour timescale.

Pancreatic β cells secrete insulin, the body's only hormone capable of lowering plasma glucose levels. Impaired or insufficient insulin secretion results in diabetes mellitus. The β cell is electrically excitable; in response to an elevation of glucose, it depolarizes and starts generating action potentials. The electrophysiology of mouse β cells and the cell's role in insulin secretion have been extensively investigated. More recently, similar studies have been performed on human β cells. These studies have revealed numerous and important differences between human and rodent β cells. Here we discuss the properties of human pancreatic β cells: their glucose sensing, the ion channel complement underlying glucose-induced electrical activity that culminates in exocytotic release of insulin, the cellular control of exocytosis, and the modulation of insulin secretion by circulating hormones and locally released neurotransmitters. Finally, we consider the pathophysiology of insulin secretion and the interactions between genetics and environmental factors that may explain the current diabetes epidemic.

Tissue damage evokes an inflammatory response that promotes the removal of harmful stimuli, tissue repair, and protective behaviors to prevent further damage and encourage healing. However, inflammation may outlive its usefulness and become chronic. Chronic inflammation can lead to a host of diseases, including asthma, itch, rheumatoid arthritis, and colitis. Primary afferent sensory neurons that innervate target organs release inflammatory neuropeptides in the local area of tissue damage to promote vascular leakage, the recruitment of immune cells, and hypersensitivity to mechanical and thermal stimuli. TRPA1 channels are required for neuronal excitation, the release of inflammatory neuropeptides, and subsequent pain hypersensitivity. TRPA1 is also activated by the release of inflammatory agents from nonneuronal cells in the area of tissue injury or disease. This dual function of TRPA1 as a detector and instigator of inflammatory agents makes TRPA1 a gatekeeper of chronic inflammatory disorders of the skin, airways, and gastrointestinal tract.

Androgens play pivotal roles in the regulation of male development and physiological processes, particularly in the male reproductive system. Most biological effects of androgens are mediated by the action of nuclear androgen receptor (AR). AR acts as a master regulator of downstream androgen-dependent signaling pathway networks. This ligand-dependent transcriptional factor modulates gene expression through the recruitment of various coregulator complexes, the induction of chromatin reorganization, and epigenetic histone modifications at target genomic loci. Dysregulation of androgen/AR signaling perturbs normal reproductive development and accounts for a wide range of pathological conditions such as androgen-insensitive syndrome, prostate cancer, and spinal bulbar muscular atrophy. In this review we summarize recent advances in understanding of the epigenetic mechanisms of AR action as well as newly recognized aspects of AR-mediated androgen signaling in both men and women. In addition, we offer a perspective on the use of animal genetic model systems aimed at eventually developing novel therapeutic AR ligands.

Estrogen exhibits a broad spectrum of physiological functions ranging from regulation of the menstrual cycle and reproduction to modulation of bone density, brain function, and cholesterol mobilization. Despite the beneficial actions of endogenous estrogen, sustained exposure to exogenous estrogen is a well-established risk factor for various cancers. We summarize our current understanding of the molecular mechanisms of estrogen signaling in normal and cancer cells and discuss the major challenges to existing antiestrogen therapies.

Nutrient absorption is the basic function that drives mammalian intestinal biology. To facilitate nutrient uptake, the host's epithelial barrier is composed of a single layer of cells. This constraint is problematic, as a design of this type can be easily disrupted. The solution during the course of evolution was to add numerous host defense mechanisms that can help prevent local and systemic infection. These mechanisms include specialized epithelial cells that produce a physiochemical barrier overlying the cellular barrier, robust and organized adaptive and innate immune cells, and the ability to mount an inflammatory response that is commensurate with a specific threat level. The autophagy pathway is a critical cellular process that strongly influences all these functions. Therefore, a fundamental understanding of the components of this pathway and their influence on inflammation, immunity, and barrier function will facilitate our understanding of homeostasis in the gastrointestinal tract.

The small and large intestines are tubular organs composed of several tissue types. The columnar epithelium that lines the inner surface of the intestines distinguishes the digestive physiology of each region of the intestine and consists of several distinct cell types that are rapidly and continually renewed by intestinal stem cells that reside near the base of the crypts of Lieberkühn. Notch signaling controls the fate of intestinal stem cells by regulating the expression of Hes genes and by repressing Atoh1. Alternate models of Notch pathway control of cell fate determination are presented. Roles for Notch signaling in development of the intestine, including mesenchymal and neural cells, are discussed. The oncogenic activities of Notch in colorectal cancer, as well as the tumor suppressive activities of Atoh1, are reviewed. Therapeutic targeting of the Notch pathway in colorectal cancers is discussed, along with potential caveats.

Paneth cells are highly specialized epithelial cells of the small intestine, where they coordinate many physiological functions. First identified more than a century ago on the basis of their readily discernible secretory granules by routine histology, these cells are located at the base of the crypts of Lieberkühn, tiny invaginations that line the mucosal surface all along the small intestine. Investigations over the past several decades determined that these cells synthesize and secrete substantial quantities of antimicrobial peptides and proteins. More recent studies have determined that these antimicrobial molecules are key mediators of host-microbe interactions, including homeostatic balance with colonizing microbiota and innate immune protection from enteric pathogens. Perhaps more intriguing, Paneth cells secrete factors that help sustain and modulate the epithelial stem and progenitor cells that cohabitate in the crypts and rejuvenate the small intestinal epithelium. Dysfunction of Paneth cell biology contributes to the pathogenesis of chronic inflammatory bowel disease.

X-ray crystal structures for the soluble amino-terminal and ligand-binding domains of glutamate receptor ion channels, combined with a 3.6-Å-resolution structure of the full-length AMPA receptor GluA2 homotetramer, provide unique insights into the mechanisms of the assembly and function of glutamate receptor ion channels. Increasingly sophisticated biochemical, computational, and electrophysiological experiments are beginning to reveal the mechanism of action of partial agonists and suggest new models for the mechanism of action of allosteric modulators. Newly identified NMDA receptor ligands acting at novel sites offer hope for the development of subtype-selective modulators. The many unresolved issues include the role of the amino-terminal domain in AMPA receptor signaling and the mechanisms by which auxiliary proteins regulate receptor activity. The structural basis for ion permeation and ion channel block also remain areas of uncertainty, and despite substantial progress, molecular dynamics simulations have yet to reveal how glutamate binding opens the ion channel pore.

Modern neuroscience has demonstrated how the adult brain has the ability to profoundly remodel its neurons in response to changes in external stimuli or internal states. However, adult brain plasticity, although possible throughout life, remains restricted mostly to subcellular levels rather than affecting the entire cell. New neurons are continuously generated in only a few areas of the adult brain—the olfactory bulb and the dentate gyrus—where they integrate into already functioning circuitry. In these regions, adult neurogenesis adds another dimension of plasticity that either complements or is redundant to the classical molecular and cellular mechanisms of plasticity. This review extracts clues regarding the contribution of adult-born neurons to the different circuits of the olfactory bulb and specifically how new neurons participate in existing computations and enable new computational functions.

Migraine is a collection of perplexing neurological conditions in which the brain and its associated tissues have been implicated as major players during an attack. Once considered exclusively a disorder of blood vessels, compelling evidence has led to the realization that migraine represents a highly choreographed interaction between major inputs from both the peripheral and central nervous systems, with the trigeminovascular system and the cerebral cortex among the main players. Advances in in vivo and in vitro technologies have informed us about the significance to migraine of events such as cortical spreading depression and activation of the trigeminovascular system and its constituent neuropeptides, as well as about the importance of neuronal and glial ion channels and transporters that contribute to the putative cortical excitatory/inhibitory imbalance that renders migraineurs susceptible to an attack. This review focuses on emerging concepts that drive the science of migraine in both a mechanistic direction and a therapeutic direction.

Regulated exocytosis and endocytosis are critical to the function of many intercellular networks, particularly the complex neural circuits underlying mammalian behavior. Kiss-and-run (KR) is an unconventional fusion between secretory vesicles and a target membrane that releases intravesicular content through a transient, nanometer-sized fusion pore. The fusing vesicle retains its gross shape, precluding full integration into the planar membrane, and enough molecular components for rapid retrieval, reacidification, and reuse. KR makes judicious use of finite presynaptic resources, and mounting evidence suggests that it influences synaptic information transfer. Here we detail emerging perspectives on KR and its role in neurotransmission. We additionally formulate a restraining force hypothesis as a plausible mechanistic basis for KR and its physiological modulation in small nerve terminals. Clarification of the mechanism and function of KR has bearing on understanding the kinetic transitions underlying SNARE-mediated fusion, interactions between vesicles and their local environment, and the influence of release dynamics on neural information processing.

Breathing is an essential behavior that presents a unique opportunity to understand how the nervous system functions normally, how it balances inherent robustness with a highly regulated lability, how it adapts to both rapidly and slowly changing conditions, and how particular dysfunctions result in disease. We focus on recent advancements related to two essential sites for respiratory rhythmogenesis: (a) the preBötzinger Complex (preBötC) as the site for the generation of inspiratory rhythm and (b) the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) as the site for the generation of active expiration.

Luminal acidification is of pivotal importance for the physiology of the secretory and endocytic pathways and its diverse trafficking events. Acidification by the proton-pumping V-ATPase requires charge compensation by counterion currents that are commonly attributed to chloride. The molecular identification of intracellular chloride transporters and the improvement of methodologies for measuring intraorganellar pH and chloride have facilitated the investigation of the physiology of vesicular chloride transport. New data question the requirement of chloride for pH regulation of various organelles and furthermore ascribe functions to chloride that are beyond merely electrically shunting the proton pump. This review surveys the currently established and proposed intracellular chloride transporters and gives an overview of membrane-trafficking steps that are affected by the perturbation of chloride transport. Finally, potential mechanisms of membrane-trafficking modulation by chloride are discussed and put into the context of organellar ion homeostasis in general.