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  • Towards Precision Medicine for Hypertension: A Review of Genomic, Epigenomic, and Microbiomic Effects on Blood Pressure in Experimental Rat Models and Humans
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    Sandosh Padmanabhan, Bina Joe

    Compelling evidence for the inherited nature of essential hypertension has led to extensive research in rats and humans. Rats have served as the primary model for research on the genetics of hypertension resulting in identification of genomic regions that are causally associated with hypertension. In more recent times, genome-wide studies in humans have also begun to improve our understanding of the inheritance of polygenic forms of hypertension. Based on the chronological progression of research into the genetics of hypertension as the “structural backbone,” this review catalogs and discusses the rat and human genetic elements mapped and implicated in blood pressure regulation. Furthermore, the knowledge gained from these genetic studies that provide evidence to suggest that much of the genetic influence on hypertension residing within noncoding elements of our DNA and operating through pervasive epistasis or gene-gene interactions is highlighted. Lastly, perspectives on current thinking that the more complex “triad” of the genome, epigenome, and the microbiome operating to influence the inheritance of hypertension, is documented. Overall, the collective knowledge gained from rats and humans is disappointing in the sense that major hypertension-causing genes as targets for clinical management of essential hypertension may not be a clinical reality. On the other hand, the realization that the polygenic nature of hypertension prevents any single locus from being a relevant clinical target for all humans directs future studies on the genetics of hypertension towards an individualized genomic approach.

    更新日期:2017-09-20
  • Junctional Adhesion Molecules (JAMs): Cell Adhesion Receptors With Pleiotropic Functions in Cell Physiology and Development
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    Klaus Ebnet

    Junctional adhesion molecules (JAM)-A, -B and -C are cell-cell adhesion molecules of the immunoglobulin superfamily which are expressed by a variety of tissues, both during development and in the adult organism. Through their extracellular domains, they interact with other adhesion receptors on opposing cells. Through their cytoplasmic domains, they interact with PDZ domain-containing scaffolding and signaling proteins. In combination, these two properties regulate the assembly of signaling complexes at specific sites of cell-cell adhesion. The multitude of molecular interactions has enabled JAMs to adopt distinct cellular functions such as the regulation of cell-cell contact formation, cell migration, or mitotic spindle orientation. Not surprisingly, JAMs regulate diverse processes such as epithelial and endothelial barrier formation, hemostasis, angiogenesis, hematopoiesis, germ cell development, and the development of the central and peripheral nervous system. This review summarizes the recent progress in the understanding of JAMs, including their characteristic structural features, their molecular interactions, their cellular functions, and their contribution to a multitude of processes during vertebrate development and homeostasis.

    更新日期:2017-09-20
  • Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    Leonard K. Kaczmarek, Yalan Zhang

    The intrinsic electrical characteristics of different types of neurons are shaped by the K+ channels they express. From among the more than 70 different K+ channel genes expressed in neurons, Kv3 family voltage-dependent K+ channels are uniquely associated with the ability of certain neurons to fire action potentials and to release neurotransmitter at high rates of up to 1,000 Hz. In general, the four Kv3 channels Kv3.1–Kv3.4 share the property of activating and deactivating rapidly at potentials more positive than other channels. Each Kv3 channel gene can generate multiple protein isoforms, which contribute to the high-frequency firing of neurons such as auditory brain stem neurons, fast-spiking GABAergic interneurons, and Purkinje cells of the cerebellum, and to regulation of neurotransmitter release at the terminals of many neurons. The different Kv3 channels have unique expression patterns and biophysical properties and are regulated in different ways by protein kinases. In this review, we cover the function, localization, and modulation of Kv3 channels and describe how levels and properties of the channels are altered by changes in ongoing neuronal activity. We also cover how the protein-protein interaction of these channels with other proteins affects neuronal functions, and how mutations or abnormal regulation of Kv3 channels are associated with neurological disorders such as ataxias, epilepsies, schizophrenia, and Alzheimer’s disease.

    更新日期:2017-09-13
  • Quantal Fluctuations in Central Mammalian Synapses: Functional Role of Vesicular Docking Sites
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    Camila Pulido, Alain Marty

    Quantal fluctuations are an integral part of synaptic signaling. At the frog neuromuscular junction, Bernard Katz proposed that quantal fluctuations originate at “reactive sites” where specific structures of the presynaptic membrane interact with synaptic vesicles. However, the physical nature of reactive sites has remained unclear, both at the frog neuromuscular junction and at central synapses. Many central synapses, called simple synapses, are small structures containing a single presynaptic active zone and a single postsynaptic density of receptors. Several lines of evidence indicate that simple synapses may release several synaptic vesicles in response to a single action potential. However, in some synapses at least, each release event activates a significant fraction of the postsynaptic receptors, giving rise to a sublinear relation between vesicular release and postsynaptic current. Partial receptor saturation as well as synaptic jitter gives to simple synapse signaling the appearance of a binary process. Recent investigations of simple synapses indicate that the number of released vesicles follows binomial statistics, with a maximum reflecting the number of docking sites present in the active zone. These results suggest that at central synapses, vesicular docking sites represent the reactive sites proposed by Katz. The macromolecular architecture and molecular composition of docking sites are presently investigated with novel combinations of techniques. It is proposed that variations in docking site numbers are central in defining intersynaptic variability and that docking site occupancy is a key parameter regulating short-term synaptic plasticity.

    更新日期:2017-08-23
  • Notch Signaling in Development, Tissue Homeostasis, and Disease
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    Chris Siebel, Urban Lendahl

    Notch signaling is an evolutionarily highly conserved signaling mechanism, but in contrast to signaling pathways such as Wnt, Sonic Hedgehog, and BMP/TGF-β, Notch signaling occurs via cell-cell communication, where transmembrane ligands on one cell activate transmembrane receptors on a juxtaposed cell. Originally discovered through mutations in Drosophila more than 100 yr ago, and with the first Notch gene cloned more than 30 yr ago, we are still gaining new insights into the broad effects of Notch signaling in organisms across the metazoan spectrum and its requirement for normal development of most organs in the body. In this review, we provide an overview of the Notch signaling mechanism at the molecular level and discuss how the pathway, which is architecturally quite simple, is able to engage in the control of cell fates in a broad variety of cell types. We discuss the current understanding of how Notch signaling can become derailed, either by direct mutations or by aberrant regulation, and the expanding spectrum of diseases and cancers that is a consequence of Notch dysregulation. Finally, we explore the emerging field of Notch in the control of tissue homeostasis, with examples from skin, liver, lung, intestine, and the vasculature.

    更新日期:2017-08-17
  • Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    Kazuo Okamoto, Tomoki Nakashima, Masahiro Shinohara, Takako Negishi-Koga, Noriko Komatsu, Asuka Terashima, Shinichiro Sawa, Takeshi Nitta, Hiroshi Takayanagi

    The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-κB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression. We also focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system.

    更新日期:2017-08-17
  • Role of Inactivity in Chronic Diseases: Evolutionary Insight and Pathophysiological Mechanisms
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    Frank W. Booth, Christian K. Roberts, John P. Thyfault, Gregory N. Ruegsegger, Ryan G. Toedebusch

    This review proposes that physical inactivity could be considered a behavior selected by evolution for resting, and also selected to be reinforcing in life-threatening situations in which exercise would be dangerous. Underlying the notion are human twin studies and animal selective breeding studies, both of which provide indirect evidence for the existence of genes for physical inactivity. Approximately 86% of the 325 million in the United States (U.S.) population achieve less than the U.S. Government and World Health Organization guidelines for daily physical activity for health. Although underappreciated, physical inactivity is an actual contributing cause to at least 35 unhealthy conditions, including the majority of the 10 leading causes of death in the U.S. First, we introduce nine physical inactivity-related themes. Next, characteristics and models of physical inactivity are presented. Following next are individual examples of phenotypes, organ systems, and diseases that are impacted by physical inactivity, including behavior, central nervous system, cardiorespiratory fitness, metabolism, adipose tissue, skeletal muscle, bone, immunity, digestion, and cancer. Importantly, physical inactivity, itself, often plays an independent role as a direct cause of speeding the losses of cardiovascular and strength fitness, shortening of healthspan, and lowering of the age for the onset of the first chronic disease, which in turn decreases quality of life, increases health care costs, and accelerates mortality risk.

    更新日期:2017-08-17
  • PROPERTIES OF THE TRPV4 ACTIVATOR GSK1016790A AND the TRPV4 ANTAGONIST GSK2193874
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    Kevin S. Thorneloe, Mui Cheung, Dennis A. Holt, Robert N. Willette

    to the editor: We write in response to the recent article by White, Cibelli, Urban, Nilius, McGeown, and Nagy ([4][1]). We commend the authors for compiling such a wide literary review on this interesting ion channel, TRPV4. However, we have read with concern the description of the properties of the

    更新日期:2017-08-17
  • REPLY TO THORNELOE ET AL.
    Physiol. Rev. (IF 27.312) Pub Date : 2017-10-01
    John P. M. White, Mario Cibelli, Laszlo Urban, Bernd Nilius, Graham McGeown, Istvan Nagy

    to the editor: At the outset, we are, of course, happy to correct the molecular representation, and referencing, of the GSK drugs mentioned in [FIGURE 7][1], as follows: ![Figure][2]![Figure][2] Thornloe and colleagues complain that we have failed to recognize the efficacy of

    更新日期:2017-08-17
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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