Lithium- an Update on the Mechanisms of Action Part One: Pharmacology and Signal Transduction
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Apoptosis in the Resolution of Systemic Inflammation
Apoptosis in the Resolution of Systemic Inflammation J. c. Marshall and R. W. G. Watson Introduction Admission to a contemporary leU is precipitated by a heterogeneous group of dis ease processes, yet the final common pathway to death is strikingly similar [I). Fully 80% of all leu deaths occur in association with the multiple organ dysfunction syn drome (MODS) [2), a poorly understood process characterized by the development of progressive physiologic dysfunction in organ systems initially unaffected by the primary disease process. Activation of a host inflammatory response by infection, injury, or ischemia, invariably proceeds the development of MODS [3). The proxi mate causes of organ injury are not bacterial products, but the same endogenous host-derived mediators of inflammation that are responsible for containing an in fectious challenge and initiating the process of tissue repair. MODS can be concep tualized as the consequence of an overly activated or inappropriately prolonged systemic inflammatory response, therefore an understanding of the mechanisms underlying the resolution of inflammation is important to the development of clini cal strategies to prevent the syndrome. The Resolution of Inflammation Mechanisms As important to the host as the ability to activate an efficient response to an exoge nous threat, is the ability to terminate that response once the threat has passed. Both humoral and cellular counter-inflammatory mechanisms have been identified. Monocyte-mediated non-specific responses are regulated through autocrine and paracrine pathways involving the release of counter-inflammatory mediators such as lL-IO [4) or lL-lra [5) that restore the cell to a resting state. For the neutrophil, however, the expression of an inflammatory response results both in the extravasa tion of large numbers of cells into an inflammatory focus, and in the activation of these cells for antimicrobial activity. -
Odorant Receptors: Regulation, Signaling, and Expression Michele Lynn Rankin Louisiana State University and Agricultural and Mechanical College, [email protected]
Louisiana State University LSU Digital Commons LSU Doctoral Dissertations Graduate School 2002 Odorant receptors: regulation, signaling, and expression Michele Lynn Rankin Louisiana State University and Agricultural and Mechanical College, [email protected] Follow this and additional works at: https://digitalcommons.lsu.edu/gradschool_dissertations Recommended Citation Rankin, Michele Lynn, "Odorant receptors: regulation, signaling, and expression" (2002). LSU Doctoral Dissertations. 540. https://digitalcommons.lsu.edu/gradschool_dissertations/540 This Dissertation is brought to you for free and open access by the Graduate School at LSU Digital Commons. It has been accepted for inclusion in LSU Doctoral Dissertations by an authorized graduate school editor of LSU Digital Commons. For more information, please [email protected]. ODORANT RECEPTORS: REGULATION, SIGNALING, AND EXPRESSION A Dissertation Submitted to the Graduate Faculty of the Louisiana State University and Agricultural and Mechanical College in partial fulfillment of the requirements for the degree of Doctor of Philosophy In The Department of Biological Sciences By Michele L. Rankin B.S., Louisiana State University, 1990 M.S., Louisiana State University, 1997 August 2002 ACKNOWLEDGMENTS I would like to thank several people who participated in my successfully completing the requirements for the Ph.D. degree. I thank Dr. Richard Bruch for giving me the opportunity to work in his laboratory and guiding me along during the degree program. I am very thankful for the support and generosity of my advisory committee consisting of Dr. John Caprio, Dr. Evanna Gleason, and Dr. Jaqueline Stephens. At one time or another, I performed experiments in each of their laboratories and include that work in this dissertation. -
Systematic Reconstruction of Autism Biology with Multi-Level Whole
bioRxiv preprint doi: https://doi.org/10.1101/052878; this version posted May 11, 2016. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. 1 Systematic Reconstruction of Autism Biology with Multi-Level 2 Whole Exome Analysis 3 4 Weijun Luo1,2*, Chaolin Zhang3, Cory R. Brouwer1,2 5 1Department of Bioinformatics and Genomics, UNC Charlotte, Charlotte, NC 28223 6 2UNC Charlotte Bioinformatics Service Division, North Carolina Research Campus, 7 Kannapolis, NC 28081 8 3Department of Systems Biology, Department of Biochemistry and Molecular 9 Biophysics, Center for Motor Neuron Biology and Disease, Columbia University, New 10 York, New York 10032, USA 11 *Correspondence: [email protected] 12 13 14 Abstract 15 Whole exome/genome studies on autism spectrum disorder (ASD) identified thousands of 16 variants, yet not a coherent and systematic disease mechanism. We conduct novel 17 integrated analyses across multiple levels on ASD exomes. These mutations do not recur 18 or replicate at variant level, but significantly and increasingly so at gene and pathway 19 level. Genetic association reveals a novel gene+pathway dual-hit model, better explaining 20 ASD risk than the well-accepted mutation burden model. 21 In multiple analyses with independent datasets, hundreds of variants or genes consistently 22 converge to several canonical pathways. Unlike the reported gene groups or networks, 23 these pathways define novel, relevant, recurrent and systematic ASD biology. At sub- 24 pathway level, most variants disrupt the pathway-related gene functions, and multiple 25 interacting variants spotlight key modules, e.g. -
Regulation of Neuronal Communication by G Protein-Coupled Receptors ⇑ Yunhong Huang, Amantha Thathiah
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 589 (2015) 1607–1619 journal homepage: www.FEBSLetters.org Review Regulation of neuronal communication by G protein-coupled receptors ⇑ Yunhong Huang, Amantha Thathiah VIB Center for the Biology of Disease, Leuven, Belgium Center for Human Genetics (CME) and Leuven Institute for Neurodegenerative Diseases (LIND), University of Leuven (KUL), Leuven, Belgium article info abstract Article history: Neuronal communication plays an essential role in the propagation of information in the brain and Received 31 March 2015 requires a precisely orchestrated connectivity between neurons. Synaptic transmission is the mech- Revised 5 May 2015 anism through which neurons communicate with each other. It is a strictly regulated process which Accepted 5 May 2015 involves membrane depolarization, the cellular exocytosis machinery, neurotransmitter release Available online 14 May 2015 from synaptic vesicles into the synaptic cleft, and the interaction between ion channels, G Edited by Wilhelm Just protein-coupled receptors (GPCRs), and downstream effector molecules. The focus of this review is to explore the role of GPCRs and G protein-signaling in neurotransmission, to highlight the func- tion of GPCRs, which are localized in both presynaptic and postsynaptic membrane terminals, in reg- Keywords: G protein-coupled receptors ulation of intrasynaptic and intersynaptic communication, and to discuss the involvement of G-proteins astrocytic GPCRs in the regulation of neuronal communication. Neuronal communication Ó 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. Synaptic transmission Signaling Astrocytes Neurons Autoreceptors Neurotransmitters 1. -
Biochem II Signaling Intro and Enz Receptors
Signal Transduction What is signal transduction? Binding of ligands to a macromolecule (receptor) “The secret life is molecular recognition; the ability of one molecule to “recognize” another through weak bonding interactions.” Linus Pauling Pleasure or Pain – it is the receptor ligand recognition So why do cells need to communicate? -Coordination of movement bacterial movement towards a chemical gradient green algae - colonies swimming through the water - Coordination of metabolism - insulin glucagon effects on metabolism -Coordination of growth - wound healing, skin. blood and gut cells Hormones are chemical signals. 1) Every different hormone binds to a specific receptor and in binding a significant alteration in receptor conformation results in a biochemical response inside the cell 2) This can be thought of as an allosteric modification with two distinct conformations; bound and free. Log Dose Response • Log dose response (Fractional Bound) • Measures potency/efficacy of hormone, agonist or antagonist • If measuring response, potency (efficacy) is shown differently Scatchard Plot Derived like kinetics R + L ó RL Used to measure receptor binding affinity KD (KL – 50% occupancy) in presence or absence of inhibitor/antagonist (B = Receptor bound to ligand) 3) The binding of the hormone leads to a transduction of the hormone signal into a biochemical response. 4) Hormone receptors are proteins and are typically classified as a cell surface receptor or an intracellular receptor. Each have different roles and very different means of regulating biochemical / cellular function. Intracellular Hormone Receptors The steroid/thyroid hormone receptor superfamily (e.g. glucocorticoid, vitamin D, retinoic acid and thyroid hormone receptors) • Protein receptors that reside in the cytoplasm and bind the lipophilic steroid/thyroid hormones. -
Peptide and Amine Actions on the Neurogenic Limulus Heart: Biochemical Mechanisms of Modulation James Richard Groome University of New Hampshire, Durham
University of New Hampshire University of New Hampshire Scholars' Repository Doctoral Dissertations Student Scholarship Spring 1988 Peptide and amine actions on the neurogenic Limulus heart: Biochemical mechanisms of modulation James Richard Groome University of New Hampshire, Durham Follow this and additional works at: https://scholars.unh.edu/dissertation Recommended Citation Groome, James Richard, "Peptide and amine actions on the neurogenic Limulus heart: Biochemical mechanisms of modulation" (1988). Doctoral Dissertations. 1532. https://scholars.unh.edu/dissertation/1532 This Dissertation is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Doctoral Dissertations by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. INFORMATION TO USERS The most advanced technology has been used to photo graph and reproduce this manuscript from the microfilm master. UMI films the original text directly from the copy submitted. Thus, some dissertation copies are in typewriter face, while others may be from a computer printer. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyrighted material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are re produced by sectioning the original, beginning at the upper left-hand corner and continuing from left to right in equal sections with small overlaps. Each oversize page is available as one exposure on a standard 35 mm slide or as a 17" x 23" black and white photographic print for an additional charge. -
Receptor-Mediated Release of Inositol Phosphates in the Cochlear and Vestibular Sensory Epithelia of the Rat
207 Hearing Research, 69 (1993) 207-214 0 1993 Elsevier Science Publishers B.V. All rights reserved 037%5955/93/$06.00 HEARES 01970 Receptor-mediated release of inositol phosphates in the cochlear and vestibular sensory epithelia of the rat Kaoru Ogawa and Jochen Schacht Kresge Hearing Research Institute, University of Michigan, Ann Arbor, Michigan, USA (Received 19 January 1993; Revision received 3 May 1993; Accepted 7 May 1993) Various neurotransmitters, hormones and other modulators involved in intercellular communication exert their biological action at receptors coupled to phospholipase C (PLC). This enzyme catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdInsP,) to inositol 1,4,5_trisphosphate (InsP,) and 1,2-diacylglycerol (DG) which act as second messengers. In the organ of Corti of the guinea pig, the InsP, second messenger system is linked to muscarinic cholinergic and Pay purinergic receptors. However, nothing is known about the the InsP, second messenger system in the vestibule. In this study, the receptor-mediated release of inositol phosphates (InsPs) in the vestibular sensory epithelia was compared to that in the cochlear sensory epithelia of Fischer-344 rats. After preincubation of the isolated intact tissues with myo-[“H]in- ositol, stimulation with the cholinergic agonist carbamylcholine or the P, purinergic agonist ATP-y-S resulted in a concentration-dependent increase in the formation of [3H]InsPs in both epithelia. Similarly, the muscarinic cholinergic agonist muscarine enhanced InsPs release in both organs, while the nicotinic cholinergic agonist dimethylphenylpiperadinium (DMPP) was ineffective. The muscarinic cholinergic antagonist atropine completely suppressed the InsPs release induced by carbamylcholine, while the nicotinic cholinergic antagonist mecamylamine was ineffective. -
Chapter 5 Control of Cells by Chemical Messengers = How Hormones and Other Signals Work
Chapter 5 Control of Cells by Chemical Messengers = How hormones and other signals work Intercellular Communication = Intercellular Signal Transmission •Chemical communication •Electrical communication Intercellular signal transmission • Chemical transmission – Chemical signals • Neurotransmitters: Intercellular signal transmission • Chemical transmission – Chemical signals • Neurotransmitters: • Humoral factors: – Hormones – Cytokines – Bioactivators Intercellular signal transmission • Chemical transmission – Chemical signals • Neurotransmitters: • Humoral factors: • Gas: NO, CO, etc. Communication requires: signals (ligands) and receptors (binding proteins). The chemical properties of a ligand predict its binding site: • Hydrophobic/lipid-soluble: cytosolic or nuclear receptors examples: steroid hormones, thyroid hormones… • Hydrophilic/lipid-insoluble: membrane-spanning receptors examples: epinephrine, insulin… Receptors are proteins that can bind only specific ligands and they are linked to response systems. • Hydrophobic signals typically change gene expression, leading to slow but sustained responses. • Hydrophilic signals typically activate rapid, short-lived responses that can be of drastic impact. Intercellular signal transmission • Chemical transmission – Chemical signals – Receptors • Membrane receptors • Intracellular receptors Intercellular signal transmission • Electrical transmission Gap junction Cardiac Muscle Low Magnification View The intercalated disk is made of several types of intercellular junctions. The gap junction -
Science Journals
SCIENCE ADVANCES | RESEARCH ARTICLE GENETICS Copyright © 2018 The Authors, some Systematic reconstruction of autism biology from rights reserved; exclusive licensee massive genetic mutation profiles American Association for the Advancement 1,2 3 4 1,2 of Science. No claim to Weijun Luo, * Chaolin Zhang, Yong-hui Jiang, Cory R. Brouwer original U.S. Government Works. Distributed Autism spectrum disorder (ASD) affects 1% of world population and has become a pressing medical and social pro- under a Creative blem worldwide. As a paradigmatic complex genetic disease, ASD has been intensively studied and thousands of gene Commons Attribution mutations have been reported. Because these mutations rarely recur, it is difficult to (i) pinpoint the fewer disease- NonCommercial causing versus majority random events and (ii) replicate or verify independent studies. A coherent and systematic License 4.0 (CC BY-NC). understanding of autism biology has not been achieved. We analyzed 3392 and 4792 autism-related mutations from two large-scale whole-exome studies across multiple resolution levels, that is, variants (single-nucleotide), genes (protein- coding unit), and pathways (molecular module). These mutations do not recur or replicate at the variant level, but sig- nificantly and increasingly do so at gene and pathway levels. Genetic association reveals a novel gene + pathway dual-hit model, where the mutation burden becomes less relevant. In multiple independent analyses, hundreds of variants or genes repeatedly converge to several canonical pathways, either novel or literature-supported. These pathways define Downloaded from recurrent and systematic ASD biology, distinct from previously reported gene groups or networks. They also present a catalog of novel ASD risk factors including 118 variants and 72 genes. -
Theories of Depression by Richard H
Theories of Depression by Richard H. Hall, 1998 Monamine/5-HT Hypothesis Just as with schizophrenia, the most popular neurophysiological theory of depression follows from the drugs that are used to treat it. The evolution of antidepressant drugs has, in some ways, been the systematic narrowing down of monoamines to Serotonin. MAO inhibitors are Dopamine-Epinephrine-Norephinephrine-Seratonin agonists. Tricyclic Antidepressants are Norepinephrine-Serotonin agonists, and, finally SSRIs act as Serotonin (5-HT) agonists. Thus, the monoamine hypothesis has evolved in the same way, so that today one popular theory of depression, the Monoamine Hypothesis, is that depression is the result of underactivity of monoamines, especially 5-HT. Besides the fact that antidepression drugs are all monoamine agonists, there is other evidence that supports the theory. First, Reserpine, a monoamine antagonist, which was used to treat things like high blood pressure, is rarely used at the present time due to the fact that depression is a common side effect. Thus, not only can monoamine agonists decrease depression, but monoamine antagonists (Reserpine) can induce depression. Another piece of evidence in support of the Monoamine Hypothesis is that levels of 5-HT, as measured by its metabolites, seem to be correlated with depression. For example, patients who have low levels of a 5-HT metabolite were found to be more likely to have committed suicide. It often takes two to three weeks for antidepressant drugs to effectively treat depression. This is a difficult phenomenon to explain within the context of the monoamine hypothesis. Presumably, in response to monoamine agonists these neurotransmitter levels increase right away, and, if depression is caused by low levels of the neurotransmitter, then depression should decrease as the levels of monoamines increase. -
Sustained Administration of Pramipexole Modifies the Spontaneous Firing of Dopamine, Norepinephrine, and Serotonin Neurons in the Rat Brain
Neuropsychopharmacology (2009) 34, 651–661 & 2009 Nature Publishing Group All rights reserved 0893-133X/09 $32.00 www.neuropsychopharmacology.org Sustained Administration of Pramipexole Modifies the Spontaneous Firing of Dopamine, Norepinephrine, and Serotonin Neurons in the Rat Brain ,1 1 1,2 O Chernoloz* , M El Mansari and P Blier 1 2 Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ontario, Canada Pramipexole (PPX) is a D2/D3 receptor agonist that has been shown to be effective in the treatment of depression. Serotonin (5-HT), norepinephrine (NE) and dopamine (DA) systems are known to be involved in the pathophysiology and treatment of depression. Due to reciprocal interactions between these neuronal systems, drugs selectively targeting one system-specific receptor can indirectly modify the firing activity of neurons that contribute to firing patterns in systems that operate via different neurotransmitters. It was thus hypothesized that PPX would alter the firing rate of DA, NE and 5-HT neurons. To test this hypothesis, electrophysiological experiments were carried out in anesthetized rats. Subcutaneously implanted osmotic minipumps delivered PPX at a dose of 1 mg/kg per day for 2 or 14 days. After a 2-day treatment with PPX the spontaneous neuronal firing of DA neurons was decreased by 40%, NE neuronal firing by 33% and the firing rate of 5-HT neurons remained unaltered. After 14 days of PPX treatment, the firing rate of DA had recovered as well as that of NE, whereas the firing rate of 5-HT neurons was increased by 38%. -
Drugs, the Brain, and Behavior
Drugs, The Brain, and Behavior John Nyby Department of Biological Sciences Lehigh University What is a drug? Difficult to define Know it when you see it Neuroactive vs Non-Neuroactive drugs Two major categories of neuroactive drugs: Therapeutic Drugs Recreational Drugs (Drugs of Abuse) Both types of neuroactive drugs affect neural functioning and behavior How does a drug affect behavior Drug Behavioral (Antidepressant) Outcome (Capable of positive emotions) Different Levels at which drug effects in the brain can be studied Molecular Cellular Organismal events Events Events “Good” Therapeutic Drugs vs “Bad” Addictive drugs No clear boundary! All “good” drugs have undesirable side effects Many “good” drugs can be addictive (i.e. “bad”) under the right circumstances (i.e. Rush Limbaugh and oxycontin) How does Drug Enforcement Administration (DEA) decide whether a drug is a “good” therapeutic drug or a “bad” illegal drug. A “bad” drug in the US can be a good drug in other countries Neuroactive Drugs Work by Altering Chemical Signaling in the Brain Two Classes of Chemical Signals in the brain Neurotransmitters Neurohormones Two Ways a Drug Affects Neural Signaling Agonist for chemical signal Antagonist for chemical Signal In order to understand drug action must have a good understanding of chemical signaling in brain Neuronal communication Three Ways that information is transmitted in a Neuron Synapse Neuron Most neuroactive drugs act by altering synaptic transmission Generalized Synapse (Major Drug Events) Most neurotransmitters are either AA, modified AA, or peptides Neurotransmitter Agonists Peptide Neurotransmitter Antagonists in vesicle 1. serve as precursors AA 1. block synthetic enzymes 2. block degradative enzymes in cytoplasm 2.