Annual Review of Physiology - Volume 71, 2009

Biological sex plays an important role in normal cardiac physiology as well as in the heart's response to cardiac disease. Women generally have better cardiac function and survival than do men in the face of cardiac disease; however, this sex difference is lost when comparing postmenopausal women with age-matched men. Animal models of cardiac disease mirror what is seen in humans. Sex steroid hormones contribute significantly to sex-based differences in cardiac disease outcomes. Estrogen is generally considered to be cardioprotective, whereas testosterone is thought to be detrimental to heart function. Environmental estrogen-like molecules, such as phytoestrogens, can also affect cardiac physiology in both a positive and a negative manner.

Alternative splicing is a widespread mechanism for generating transcript diversity in higher eukaryotic genomes. The alternative splices of the large-conductance calcium-activated potassium (BK) channel have been the subject of a good deal of experimental functional characterization in the Arthropoda, Chordata, and Nematoda phyla. In this review, we examine a list of splices of the BK channel by manual curation of Unigene clusters mapped to mouse, human, chicken, Drosophila, and Caenorhabditis elegans genomes. We find that BK alternative splices do not appear to be conserved across phyla. Despite this lack of conservation, splices occur in both vertebrates and invertebrates at identical regions of the channel at experimentally established domain boundaries. The fact that, across phyla, unique splices occur at experimentally established domain boundaries suggests a prominent role for the convergent evolution of alternative splices that produce functional changes via changes in interdomain communication.

To withstand the rigors of contraction, muscle fibers have specialized protein complexes that buffer against mechanical stress and a multifaceted repair system that is rapidly activated after injury. Genetic studies first identified the mechanosensory signaling network that connects the structural elements of muscle and, more recently, have identified repair elements of muscle. Defects in the genes encoding the components of these systems lead to muscular dystrophy, a family of genetic disorders characterized by progressive muscle wasting. Although the age of onset, affected muscles, and severity vary considerably, all muscular dystrophies are characterized by muscle necrosis that overtakes the regenerative capacity of muscle. The resulting replacement of muscle by fatty and fibrous tissue leaves muscle increasingly weak and nonfunctional. This review discusses the cellular mechanisms that are primarily and secondarily disrupted in muscular dystrophy, focusing on membrane degeneration, muscle regeneration, and the repair of muscle.

Distinct potassium, anion, and calcium channels in the plasma membrane and vacuolar membrane of plant cells have been identified and characterized by patch clamping. Primarily owing to advances in Arabidopsis genetics and genomics, and yeast functional complementation, many of the corresponding genes have been identified. Recent advances in our understanding of ion channel genes that mediate signal transduction and ion transport are discussed here. Some plant ion channels, for example, ALMT and SLAC anion channel subunits, are unique. The majority of plant ion channel families exhibit homology to animal genes; such families include both hyperpolarization- and depolarization-activated Shaker-type potassium channels, CLC chloride transporters/channels, cyclic nucleotide–gated channels, and ionotropic glutamate receptor homologs. These plant ion channels offer unique opportunities to analyze the structural mechanisms and functions of ion channels. Here we review gene families of selected plant ion channel classes and discuss unique structure-function aspects and their physiological roles in plant cell signaling and transport.

Polycystins are a family of eight-transmembrane proteins united by sequence homology. The name stems from the identification of mutations in genes encoding polycystin-1 and -2 in polycystic kidney diseases. This review discusses recent topics in polycystin research, with a focus on the role of polycystin-1 and polycystin-2 in primary cilia and the cell cycle. Polycystins appear to play key roles during development, but a major question is their function in mature organs. Their roles in primary cilia, shear stress sensation, alteration of intracellular calcium, and planar cell polarity are examined. The third-hit hypothesis of polycystic kidney disease is discussed.

The mammalian olfactory system senses an almost unlimited number of chemical stimuli and initiates a process of neural recognition that influences nearly every aspect of life. This review examines the organizational principles underlying the recognition of olfactory stimuli. The olfactory system is composed of a number of distinct subsystems that can be distinguished by the location of their sensory neurons in the nasal cavity, the receptors they use to detect chemosensory stimuli, the signaling mechanisms they employ to transduce those stimuli, and their axonal projections to specific regions of the olfactory forebrain. An integrative approach that includes gene targeting methods, optical and electrophysiological recording, and behavioral analysis has helped to elucidate the functional significance of this subsystem organization for the sense of smell.

We review studies conducted in mouse and ferret that have specified roles of both the main and the accessory olfactory nervous systems in the detection and processing of body odorants (e.g., urinary pheromones, extraorbital lacrimal gland secretions, major histocompatibility complex peptide ligands, and anal scent gland secretions) that play an essential role in sex discrimination and attraction between males and females leading to mate choice and successful reproduction. We also review literature that compares the forebrain processing of inputs from the two olfactory systems in the two sexes that underlies heterosexual partner preferences. Finally, we review experiments that raise the possibility that body odorants detected by the main olfactory system contribute to mate recognition in humans.

This selective review considers herpetological papers that feature the use of chemical cues, particularly pheromones involved in reproductive interactions between potential mates. Primary examples include garter snake females that attract males, lacertid lizards and the effects of their femoral gland secretions, aquatic male newts that chemically attract females, and terrestrial salamander males that chemically persuade a female to mate. Each case study spans a number of research approaches (molecular, biochemical, behavioral) and is related to sensory processing and the physiological effects of pheromone delivery. These and related studies show that natural pheromones can be identified, validated with behavioral tests, and incorporated in research on vomeronasal functional response.

Mitochondria play central roles in energy homeostasis, metabolism, signaling, and apoptosis. Accordingly, the abundance, morphology, and functional properties of mitochondria are finely tuned to meet cell-specific energetic, metabolic, and signaling demands. This tuning is largely achieved at the level of transcriptional regulation. A highly interconnected network of transcription factors regulates a broad set of nuclear genes encoding mitochondrial proteins, including those that control replication and transcription of the mitochondrial genome. The same transcriptional network senses cues relaying cellular energy status, nutrient availability, and the physiological state of the organism and enables short- and long-term adaptive responses, resulting in adjustments to mitochondrial function and mitochondrial biogenesis. Mitochondrial dysfunction is associated with many human diseases. Characterization of the transcriptional mechanisms that regulate mitochondrial biogenesis and function can offer insights into possible therapeutic interventions aimed at modulating mitochondrial function.

Digestion of food and normal salt and water homeostasis in the body require a functional digestive tract. Recently an increasing number of studies have demonstrated a role for the calcium-sensing receptor along the entire gastrointestinal tract and its role in normal gut physiology. Detailed studies have been performed on colonic fluid transport and gastric acid secretion. We have now demonstrated that the receptor can modulate fluid secretion and absorption along the intestine and can thereby be a potent target to prevent secretory diarrhea. Recent studies have demonstrated that organic nutrients such as polyamines and l-amino acids can act as agonists by allosterically modifying the receptor. Thus, the receptor may detect nutrient availability to epithelial cells along the gastrointestinal tract and may be involved in the coordinated rapid turnover of the intestinal epithelium. Furthermore, the receptor has been suggested as a link for the mechanisms leading to calcium uptake by the colon and may thus reduce the risk for colon cancer.

Stress affects the gastrointestinal tract as part of the visceral response. Various stressors induce similar profiles of gut motor function alterations, including inhibition of gastric emptying, stimulation of colonic propulsive motility, and hypersensitivity to colorectal distension. In recent years, substantial progress has been made in our understanding of the underlying mechanisms of stress's impact on gut function. Activation of corticotropin-releasing factor (CRF) signaling pathways mediates both the inhibition of upper gastrointestinal (GI) and the stimulation of lower GI motor function through interaction with different CRF receptor subtypes. Here, we review how various stressors affect the gut, with special emphasis on the central and peripheral CRF signaling systems.

The mammalian intestine is covered by a single layer of epithelial cells that is renewed every 4–5 days. This high cell turnover makes it a very attractive and comprehensive adult organ system for the study of cell proliferation and differentiation. The intestine is composed of proliferative crypts, which contain intestinal stem cells, and villi, which contain differentiated specialized cell types. Through the recent identification of Lgr5, an intestinal stem cell marker, it is now possible to visualize stem cells and study their behavior and differentiation in a much broader context. In this review we describe the identification of intestinal stem cells. We also discuss genetic studies that have helped to elucidate those signals important for progenitor cells to differentiate into one of the specialized intestinal epithelial cell types. These studies describe a genetic hierarchy responsible for cell fate commitment in normal gut physiology. Where relevant we also mention aberrant deregulation of these molecular pathways that results in colon cancer.

Dendritic spines are the postsynaptic components of most excitatory synapses in the mammalian brain. Spines accumulate rapidly during early postnatal development and undergo a substantial loss as animals mature into adulthood. In past decades, studies have revealed that the number and size of dendritic spines are regulated by a variety of gene products and environmental factors, underscoring the dynamic nature of spines and their importance to brain plasticity. Recently, in vivo time-lapse imaging of dendritic spines in the cerebral cortex suggests that, although spines are highly plastic during development, they are remarkably stable in adulthood, and most of them last throughout life. Therefore, dendritic spines may provide a structural basis for lifelong information storage, in addition to their well-established role in brain plasticity. Because dendritic spines are the key elements for information acquisition and retention, understanding how spines are formed and maintained, particularly in the intact brain, will likely provide fundamental insights into how the brain possesses the extraordinary capacity to learn and to remember.

Endocannabinoids (eCBs) are key activity-dependent signals regulating synaptic transmission throughout the central nervous system. Accordingly, eCBs are involved in neural functions ranging from feeding homeostasis to cognition. There is great interest in understanding how exogenous (e.g., cannabis) and endogenous cannabinoids affect behavior. Because behavioral adaptations are widely considered to rely on changes in synaptic strength, the prevalence of eCB-mediated long-term depression (eCB-LTD) at synapses throughout the brain merits close attention. The induction and expression of eCB-LTD, although remarkably similar at various synapses, are controlled by an array of regulatory influences that we are just beginning to uncover. This complexity endows eCB-LTD with important computational properties, such as coincidence detection and input specificity, critical for higher CNS functions like learning and memory. In this article, we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity.

Olfaction is a critical sensory modality that allows living things to acquire chemical information from the external world. The olfactory system processes two major classes of stimuli: (a) general odorants, small molecules derived from food or the environment that signal the presence of food, fire, or predators, and (b) pheromones, molecules released from individuals of the same species that convey social or sexual cues. Chemosensory receptors are broadly classified, by the ligands that activate them, into odorant or pheromone receptors. Peripheral sensory neurons expressing either odorant or pheromone receptors send signals to separate odor- and pheromone-processing centers in the brain to elicit distinct behavioral and neuroendocrinological outputs. General odorants activate receptors in a combinatorial fashion, whereas pheromones activate narrowly tuned receptors that activate sexually dimorphic neural circuits in the brain. We review recent progress on chemosensory receptor structure, function, and circuitry in vertebrates and invertebrates from the point of view of the molecular biology and physiology of these sensory systems.

P2X receptors are membrane cation channels gated by extracellular ATP. Seven P2X receptor subunits (P2X1-7) are widely distributed in excitable and nonexcitable cells of vertebrates. They play key roles in inter alia afferent signaling (including pain), regulation of renal blood flow, vascular endothelium, and inflammatory responses. We summarize the evidence for these and other roles, emphasizing experimental work with selective receptor antagonists or with knockout mice. The receptors are trimeric membrane proteins: Studies of the biophysical properties of mutated subunits expressed in heterologous cells have indicated parts of the subunits involved in ATP binding, ion permeation (including calcium permeability), and membrane trafficking. We review our current understanding of the molecular properties of P2X receptors, including how this understanding is informed by the identification of distantly related P2X receptors in simple eukaryotes.

The study of human monogenic diseases [pseudohypoaldosteronism type 1 (PHA-1) and Liddle's syndrome] as well as mouse models mimicking the salt-losing syndrome (PHA-1) or salt-sensitive hypertension (Liddle's syndrome) have established the epithelial sodium channel ENaC as a limiting factor in vivo in the control of ionic composition of the extracellular fluid, regulation of blood volume and blood pressure, lung alveolar clearance, and airway mucociliary clearance. In this review, we discuss more specifically the activation of ENaC by serine proteases. Recent in vitro and in vivo experiments indicate that membrane-bound serine proteases are of critical importance in the activation of ENaC in different organs, such as the kidney, the lung, or the cochlea. Progress in understanding the basic mechanism of proteolytic activation of ENaC is accelerating, but uncertainty about the most fundamental aspects persists, leaving numerous still-unanswered questions.

The potassium homeostatic system is very tightly regulated. Recent studies have shed light on the sensing and molecular mechanisms responsible for this tight control. In addition to classic feedback regulation mediated by a rise in extracellular fluid (ECF) [K⁺], there is evidence for a feedforward mechanism: Dietary K⁺ intake is sensed in the gut, and an unidentified gut factor is activated to stimulate renal K⁺ excretion. This pathway may explain renal and extrarenal responses to altered K⁺ intake that occur independently of changes in ECF [K⁺]. Mechanisms for conserving ECF K⁺ during fasting or K⁺ deprivation have been described: Kidney NADPH oxidase activation initiates a cascade that provokes the retraction of K⁺ channels from the cell membrane, and muscle becomes resistant to insulin stimulation of cellular K⁺ uptake. How these mechanisms are triggered by K⁺ deprivation remains unclear. Cellular AMP kinase–dependent protein kinase activity provokes the acute transfer of K⁺ from the ECF to the ICF, which may be important in exercise or ischemia. These recent advances may shed light on the beneficial effects of a high-K⁺ diet for the cardiovascular system.

Amiloride-sensitive epithelial sodium channels (ENaC) play an important role in lung sodium transport. Sodium transport is closely regulated to maintain an appropriate fluid layer on the alveolar surface. Both alveolar type I and II cells have several different sodium-permeable channels in their apical membranes that play a role in normal lung physiology and pathophysiology. In many epithelial tissues, ENaC is formed from three subunit proteins: α, β, and γ ENaC. Part of the diversity of sodium-permeable channels in lung arises from assembling different combinations of these subunits to form channels with different biophysical properties and different mechanisms for regulation. Thus, lung epithelium has enormous flexibility to alter the magnitude of salt and water transport. In lung, ENaC is regulated by many transmitter and hormonal agents. Regulation depends upon the type of sodium channel but involves controlling the number of apical channels and/or the activity of individual channels.