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Handbook of Experimental Pharmacology

Wilfried Dinh, Barbara Albrecht-Küpper, Mihai Gheorghiade, Adriaan A Voors, Michael van der Laan, Hani N Sabbah
Adenosine exerts a variety of physiological effects by binding to cell surface G-protein-coupled receptor subtypes, namely, A1, A2a, A2b, and A3. The central physiological role of adenosine is to preclude tissue injury and promote repair in response to stress. In the heart, adenosine acts as a cytoprotective modulator, linking cardiac function to metabolic demand predominantly via activation of adenosine A1 receptors (A1Rs), which leads to inhibition of adenylate cyclase activity, modulation of protein kinase C, and opening of ATP-sensitive potassium channels...
October 22, 2016: Handbook of Experimental Pharmacology
Anika Steffen, Theresia E B Stradal, Klemens Rottner
The actin cytoskeleton is essential for morphogenesis and virtually all types of cell shape changes. Reorganization is per definition driven by continuous disassembly and re-assembly of actin filaments, controlled by major, ubiquitously operating machines. These are specifically employed by the cell to tune its activities in accordance with respective environmental conditions or to satisfy specific needs.Here we sketch some fundamental signalling pathways established to contribute to the reorganization of specific actin structures at the plasma membrane...
October 19, 2016: Handbook of Experimental Pharmacology
Irina G Tikhonova
Five G protein-coupled receptors (GPCRs) have been identified to be activated by free fatty acids (FFA). Among them, FFA1 (GPR40) and FFA4 (GPR120) bind long-chain fatty acids, FFA2 (GPR43) and FFA3 (GPR41) bind short-chain fatty acids and GPR84 binds medium-chain fatty acids. Free fatty acid receptors have now emerged as potential targets for the treatment of diabetes, obesity and immune diseases. The recent progress in crystallography of GPCRs has now enabled the elucidation of the structure of FFA1 and provided reliable templates for homology modelling of other FFA receptors...
October 19, 2016: Handbook of Experimental Pharmacology
Brian D Hudson
The free fatty acid (FFA) family of G protein coupled receptors (GPCRs) has generated significant interest for exploiting its members as potential drug targets. However, unravelling the complex pharmacology of this family of receptors has proven challenging. In recent years the use of biosensor technologies capable of assessing biological functions in living cells, and in real time, has greatly enhanced our ability to study GPCR pharmacology and function. These include genetically encoded sensors that change the intensity or wavelength of light emitted from a bioluminescent or fluorescent protein in response to a stimulus, as well as non-genetically encoded sensors able to measure more global cellular changes, such as mass redistribution within a cell...
October 19, 2016: Handbook of Experimental Pharmacology
Takafumi Hara
FFA1 is a G protein-coupled receptor activated by medium- to long-chain fatty acids. FFA1 plays important roles in various physiological processes such as insulin secretion and energy metabolism. FFA1 expressed on pancreatic β-cells and intestine contributes to insulin and incretin secretion, respectively. These physiological functions of FFA1 are interesting as an attractive drug target for type II diabetes and metabolic disorders. A number of synthetic FFA1 ligands have been developed and they have contributed to our current understanding of the physiological and pathophysiological functions of FFA1 both in in vitro and in vivo studies...
October 19, 2016: Handbook of Experimental Pharmacology
Thomas A Masters, John Kendrick-Jones, Folma Buss
Myosins are cytoskeletal motor proteins that use energy derived from ATP hydrolysis to generate force and movement along actin filaments. Humans express 38 myosin genes belonging to 12 classes that participate in a diverse range of crucial activities, including muscle contraction, intracellular trafficking, cell division, motility, actin cytoskeletal organisation and cell signalling. Myosin malfunction has been implicated a variety of disorders including deafness, hypertrophic cardiomyopathy, Usher syndrome, Griscelli syndrome and cancer...
October 19, 2016: Handbook of Experimental Pharmacology
Cong Tang, Stefan Offermanns
The short-chain fatty acid receptors FFA2 (GPR43) and FFA3 (GPR41) are activated by acetate, propionate, and butyrate. These ligands are produced by bacteria in the gut. In addition, the body itself can in particular produce acetate, and acetate plasma levels have been shown to be increased, e.g., in diabetic patients or during periods of starvation. FFA2 and FFA3 are both expressed by enteroendocrine cells and pancreatic β-cells. In addition, FFA2 is found on immune cells and adipocytes, whereas FFA3 is expressed by some peripheral neurons...
October 19, 2016: Handbook of Experimental Pharmacology
Lena Brüser, Sven Bogdan
The actin cytoskeleton provides mechanical support for cells and generates forces to drive cell shape changes and cell migration in morphogenesis. Molecular understanding of actin dynamics requires a genetically traceable model system that allows interdisciplinary experimental approaches to elucidate the regulatory network of cytoskeletal proteins in vivo. Here, we will discuss some examples of how advances in Drosophila genetics and high-resolution imaging techniques contribute to the discovery of new actin functions, signaling pathways, and mechanisms of actin regulation in vivo...
October 19, 2016: Handbook of Experimental Pharmacology
Graeme Milligan, Daniele Bolognini, Eugenia Sergeev
A large number of reviews and commentaries have highlighted the potential role of the short-chain fatty acid receptors GPR41 (FFA3) and, particularly, GPR43 (FFA2) as an interface between the intestinal microbiota and metabolic and inflammatory disorders. However, short-chain fatty acids have very modest potency and display limited selectivity between these two receptors, and studies on receptor knockout mice have resulted in non-uniform conclusions; therefore, selective and high-potency/high-affinity synthetic ligands are required to further explore the contribution of these receptors to health and disease...
October 19, 2016: Handbook of Experimental Pharmacology
Christophe Ampe, Marleen Van Troys
Actin is the central building block of the actin cytoskeleton, a highly regulated filamentous network enabling dynamic processes of cells and simultaneously providing structure. Mammals have six actin isoforms that are very conserved and thus share common functions. Tissue-specific expression in part underlies their differential roles, but actin isoforms also coexist in various cell types and tissues, suggesting specific functions and preferential interaction partners. Gene deletion models, antibody-based staining patterns, gene silencing effects, and the occurrence of isoform-specific mutations in certain diseases have provided clues for specificity on the subcellular level and its consequences on the organism level...
October 19, 2016: Handbook of Experimental Pharmacology
Mandi M Hopkins, Kathryn E Meier
The effects of fatty acids on cancer cells have been studied for decades. The roles of dietary long-chain n-3 polyunsaturated fatty acids, and of microbiome-generated short-chain butyric acid, have been of particular interest over the years. However, the roles of free fatty acid receptors (FFARs) in mediating effects of fatty acids in tumor cells have only recently been examined. In reviewing the literature, the data obtained to date indicate that the long-chain FFARs (FFA1 and FFA4) play different roles than the short-chain FFARs (FFA2 and FFA3)...
October 19, 2016: Handbook of Experimental Pharmacology
N Bishara Marzook, Timothy P Newsome
The actin cytoskeleton is a crucial part of the eukaryotic cell. Viruses depend on host cells for their replication, and, as a result, many have developed ways of manipulating the actin network to promote their spread. This chapter reviews the various ways in which viruses utilize the actin cytoskeleton at discrete steps in their life cycle, from entry into the host cell, replication, and assembly of new progeny to virus release. Various actin inhibitors that function in different ways to affect proper actin dynamics can be used to parse the role of actin at these steps...
October 19, 2016: Handbook of Experimental Pharmacology
Michel Komajda
Ivabradine is a blocker of the funny current channels in the sinoatrial node cells. This results in pure heart rate reduction when elevated without direct effect on contractility or on the vessels. It was tested in a large outcome clinical trial in stable chronic heart failure (CHF) with low ejection fraction, in sinus rhythm, on a contemporary background therapy including betablockers (SHIFT: Systolic Heart Failure Treatment with the If inhibitor Trial).The primary composite endpoint (cardiovascular mortality or heart failure hospitalization) was reduced by 18% whereas the first occurrence of heart failure hospitalizations was reduced by 26%...
October 18, 2016: Handbook of Experimental Pharmacology
Maria Schirone, Pierina Visciano, Rosanna Tofalo, Giovanna Suzzi
The consumption of food containing high amounts of histamine and other biogenic amines can cause food poisoning with different symptoms linked to the individual sensitivity and the detoxification activity. Histamine is the only biogenic amine with regulatory limits set by the European Commission in fish and fishery products, because it can lead to a fatal outcome. However, also fermented foods can be involved in outbreaks and sporadic cases of intoxication. The factors affecting the presence of histamine in food are variable and product specific including the availability of the precursor amino acid, the presence of microorganisms producing decarboxylases, and the conditions allowing their growth and enzyme production...
October 18, 2016: Handbook of Experimental Pharmacology
Leonard A Levin
Glaucoma is both the most common optic neuropathy worldwide and the most common cause of irreversible blindness in the world. The only proven treatment for glaucomatous optic neuropathy is lowering the intraocular pressure, achieved with a variety of pharmacological, laser, and surgical approaches. Over the past 2 decades there has been much basic and clinical research into achieving treatment of the underlying optic nerve damage with neuroprotective approaches. However, none has resulted in regulatory approval based on successful phase 3 studies...
October 18, 2016: Handbook of Experimental Pharmacology
Yong Park, Dorette Ellis, Brett Mueller, Dorota Stankowska, Thomas Yorio
Recently, in a poll by Research America, a significant number of individuals placed losing their eyesight as having the greatest impact on their lives more so than other conditions, such as limb loss or memory loss. When they were also asked to rank which is the worst disease that could happen to them, blindness was ranked first by African-Americans and second by Caucasians, Hispanics, and Asians. Therefore, understanding the mechanisms of disease progression in the eye is extremely important if we want to make a difference in people's lives...
October 12, 2016: Handbook of Experimental Pharmacology
John Medamana, Richard A Clark, Javed Butler
Defective vascular and cardiomyocyte function are implicated in the development and progression of both heart failure with reduced and preserved ejection fraction. Any treatment option that augments these myocardial processes may therefore be of significant value. The platelet-derived growth factor (PDGF) family is involved in a wide range of growth processes and plays a key role in both regulating angiogenesis and mesenchymal cell development. Thus, PDGF may serve as a potent therapy for heart failure. While numerous animal studies have demonstrated beneficial cardiovascular effects of growth factor therapy, promising laboratory data has not yet translated to effective therapies...
October 8, 2016: Handbook of Experimental Pharmacology
Francesco Orso, Gianna Fabbri, Aldo Pietro Maggioni
Heart failure (HF) is a major public health problem affecting more than 23 million patients worldwide. Incidence and prevalence rates vary significantly according to the source of data, but both increase with advancing age reaching, in the very elderly, prevalence rates that represent a challenge for the organization of medical care systems. Even if evidence-based treatments have improved prognosis in some patients with HF, patients with HF still need to be carefully characterized, described, and treated. Hospitalizations for acute HF are frequent and costly accounting for the vast majority of HF-related costs...
October 8, 2016: Handbook of Experimental Pharmacology
Shubha Gururaja Rao
Mitochondrial structural and functional integrity defines the health of a cell by regulating cellular metabolism. Thus, mitochondria play an important role in both cell proliferation and cell death. Cancer cells are metabolically altered compared to normal cells for their ability to survive better and proliferate faster. Resistance to apoptosis is an important characteristic of cancer cells and given the contribution of mitochondria to apoptosis, it is imperative that mitochondria could behave differently in a tumor situation...
October 8, 2016: Handbook of Experimental Pharmacology
Omar S Mabrouk
Parkinson's disease (PD) is a progressive neurodegenerative disorder that compromises multiple neurochemical substrates including dopamine, norepinephrine, serotonin, acetylcholine, and glutamate systems. Loss of these transmitter systems initiates a cascade of neurological deficits beginning with motor function and ending with dementia. Current therapies primarily address the motor symptoms of the disease via dopamine replacement therapy. Exogenous dopamine replacement brings about additional challenges since after years of treatment it almost invariably gives rise to dyskinesia as a side effect...
October 8, 2016: Handbook of Experimental Pharmacology
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