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Handbook of Experimental Pharmacology

Hirokazu Arimoto, Daiki Takahashi
Nitric oxide (NO) raises the intracellular 3',5'-cyclic guanosine monophosphate (cGMP) level through the activation of soluble guanylate cyclase and, in the presence of reactive oxygen species (ROS), reacts with biomolecules to produce nitrated cGMP derivatives. 8-Nitro-cGMP was the first endogenous cGMP derivative discovered in mammalian cells (2007) and was later found in plant cells. Among the six nitrogen atoms in this molecule, the one in the nitro group (NO2) comes from NO. This chapter asserts that this newly found cGMP is undoubtedly one of the major physiological cNMPs...
February 18, 2017: Handbook of Experimental Pharmacology
James J Galligan, Catia Sternini
Opioid drugs are prescribed extensively for pain treatment but when used chronically they induce constipation that can progress to opioid-induced bowel dysfunction. Opioid drugs interact with three classes of opioid receptors: mu opioid receptors (MORs), delta opioid receptors (DOR), and kappa opioid receptors (KORs), but opioid drugs mostly target the MORs. Upon stimulation, opioid receptors couple to inhibitory Gi/Go proteins that activate or inhibit downstream effector proteins. MOR and DOR couple to inhibition of adenylate cyclase and voltage-gated Ca(2+) channels and to activation of K(+) channels resulting in reduced neuronal activity and neurotransmitter release...
February 16, 2017: Handbook of Experimental Pharmacology
Hans Törnblom, Douglas A Drossman
Chronic abdominal pain has a widespread impact on the individual and the society. Identifying and explaining mechanisms of importance for the pain experience within a biopsychosocial context are central in order to select treatment that has a chance for symptom reduction. With current knowledge of brain-gut interactions, chronic abdominal pain, which mostly appears in functional gastrointestinal disorders, to a large extent involves pain mechanisms residing within the brain. As such, the use of centrally targeted pharmacotherapy as an effective treatment option is obvious in a selected number of patients...
February 16, 2017: Handbook of Experimental Pharmacology
Erich H Schneider, Roland Seifert
This chapter addresses cNMP hydrolysis by phosphodiesterases (PDEs) and export by multidrug resistance associated proteins (MRPs). Both mechanisms are well-established for the canonical cNMPs, cAMP, and cGMP. Increasing evidence shows that non-canonical cNMPs (specifically cCMP, cUMP) are also PDE and MRP substrates. Hydrolysis of cUMP is achieved by PDE 3A, 3B, and 9A, which possibly explains the cUMP-degrading activities previously reported for heart, adipose tissue, and brain. Regarding cCMP, the only known "conventional" (class I) PDE that hydrolyzes cCMP is PDE7A...
February 16, 2017: Handbook of Experimental Pharmacology
Jyotsna Mishra, Bong Sook Jhun, Stephen Hurst, Jin O-Uchi, György Csordás, Shey-Shing Sheu
Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex.
February 14, 2017: Handbook of Experimental Pharmacology
Amol Sharma, Satish Rao
Chronic constipation is a common, persistent condition affecting many patients worldwide, presenting significant economic burden and resulting in substantial healthcare utilization. In addition to infrequent bowel movements, the definition of constipation includes excessive straining, a sense of incomplete evacuation, failed or lengthy attempts to defecate, use of digital manoeuvres for evacuation of stool, abdominal bloating, and hard consistency of stools. After excluding secondary causes of constipation, chronic idiopathic or primary constipation can be classified as functional defecation disorder, slow-transit constipation (STC), and constipation-predominant irritable bowel syndrome (IBS-C)...
February 10, 2017: Handbook of Experimental Pharmacology
Albrecht von Hardenberg, Christoph Maack
The current therapy for patients with stable systolic heart failure is largely limited to treatments that interfere with neurohormonal activation. Critical pathophysiological hallmarks of heart failure are an energetic deficit and oxidative stress, and both may be the result of mitochondrial dysfunction. This dysfunction is not (only) the result of defect within mitochondria per se, but is in particular traced to defects in intermediary metabolism and of the regulatory interplay between excitation-contraction coupling and mitochondrial energetics, where defects of cytosolic calcium and sodium handling in failing hearts may play important roles...
February 9, 2017: Handbook of Experimental Pharmacology
Michele Senni, Emilia D'Elia, Michele Emdin, Giuseppe Vergaro
Biomarkers are increaingly being used in the management of heart failure not only for the purpose of screening, diagnosis, and risk stratification, but also as a guide to evaluate the response to treatment in the individual patient and as an entry criterion and/or a surrogate marker of efficacy in clinical trials testing novel drugs. In this chapter, we review the role of established biomarkers for heart failure management, according to the main classification of HF phenotypes, based on the measurement of left ventricular ejection fraction, including heart failure with reduced (<40%), preserved (≥50%), and, as recently proposed, mid-range (40-49%) ejection fraction...
February 9, 2017: Handbook of Experimental Pharmacology
Roland Seifert
The cyclic purine nucleotides cAMP and cGMP are well-established second messenger molecules that are generated by distinct nucleotidyl cyclases (NCs) and regulate numerous cell functions via specific effector molecules. In contrast, the existence of the cyclic pyrimidine nucleotides cCMP and cUMP has been controversial for many years. The development of highly specific and sensitive mass spectrometry methods has enabled the unequivocal detection and quantitation of cCMP and cUMP in biological systems. These cNMPs occur broadly in numerous mammalian cell lines and primary cells...
February 9, 2017: Handbook of Experimental Pharmacology
Bryan VanSchouwen, Giuseppe Melacini
The hyperpolarization-activated cyclic-nucleotide-modulated (HCN) proteins are cAMP-regulated ion channels that play a key role in nerve impulse transmission and heart rate modulation in neuronal and cardiac cells, respectively. Although they are regulated primarily by cAMP, other cyclic nucleotides such as cGMP, cCMP, and cUMP serve as partial agonists for the HCN2 and HCN4 isoforms. By competing with cAMP for binding, these non-canonical ligands alter ion channel gating, and in turn, modulate the cAMP-dependent activation profiles...
February 9, 2017: Handbook of Experimental Pharmacology
Arun K Mankan, Martina Müller, Gregor Witte, Veit Hornung
First discovered in prokaryotes and more recently in eukaryotes, cyclic dinucleotides (CDNs) constitute a unique branch of second messenger signaling systems. Within prokaryotes CDNs regulate a wide array of different biological processes, whereas in the vertebrate system CDN signaling is largely dedicated to activation of the innate immune system. In this book chapter we summarize the occurrence and signaling pathways of these small-molecule second messengers, most importantly in the scope of the mammalian immune system...
February 9, 2017: Handbook of Experimental Pharmacology
K Adam Morrow, Dara W Frank, Ron Balczon, Troy Stevens
Exoenzyme Y (ExoY) was identified as a component of the Pseudomonas aeruginosa type 3 secretion system secretome in 1998. It is a common contributor to the arsenal of type 3 secretion system effectors, as it is present in approximately 90% of Pseudomonas isolates. ExoY has adenylyl cyclase activity that is dependent upon its association with a host cell cofactor. However, recent evidence indicates that ExoY is not just an adenylyl cyclase; rather, it is a promiscuous cyclase capable of generating purine and pyrimidine cyclic nucleotide monophosphates...
February 9, 2017: Handbook of Experimental Pharmacology
Heike Bähre, Volkhard Kaever
Contemporary investigations regarding the (patho)physiological roles of the non-canonical cyclic nucleoside monophosphates (cNMP) cytidine 3',5'-cyclic monophosphate (cCMP) and uridine 3',5'-cyclic monophosphate (cUMP) have been hampered by the lack of highly specific and sensitive analytic methods for these analytes. In addition, the existence of 2',3'-cNMP besides 3',5'-cNMP has been described recently. HPLC coupled with tandem mass spectrometry (HPLC-MS/MS) is the method of choice for identification and quantification of low-molecular weight endogenous metabolites...
February 9, 2017: Handbook of Experimental Pharmacology
Beverley Greenwood-Van Meerveld, Anthony C Johnson, David Grundy
The gastrointestinal (GI) system is responsible for the digestion and absorption of ingested food and liquids. Due to the complexity of the GI tract and the substantial volume of material that could be covered under the scope of GI physiology, this chapter briefly reviews the overall function of the GI tract, and discusses the major factors affecting GI physiology and function, including the intestinal microbiota, chronic stress, inflammation, and aging with a focus on the neural regulation of the GI tract and an emphasis on basic brain-gut interactions that serve to modulate the GI tract...
February 8, 2017: Handbook of Experimental Pharmacology
Anthony C Johnson, Beverley Greenwood-Van Meerveld
Preclinical research remains an important tool for discovery and validation of novel therapeutics for gastrointestinal disorders. While in vitro assays can be used to verify receptor-ligand interactions and test for structural activity of new compounds, only whole-animal studies can demonstrate drug efficacy within the gastrointestinal system. Most major gastrointestinal disorders have been modeled in animals; however the translational relevance of each model is not equal. The purpose of this chapter is to provide a critical evaluation of common animal models that are being used to develop pharmaceuticals for gastrointestinal disorders...
February 8, 2017: Handbook of Experimental Pharmacology
Chenbo Zeng, Elizabeth S McDonald, Robert H Mach
The sigma-2 (σ2) receptor has been validated as a biomarker of the proliferative status of solid tumors. Therefore, radiotracers having a high affinity and high selectivity for σ2 receptors have the potential to assess the proliferative status of human tumors using noninvasive imaging techniques such as Positron Emission Tomography (PET). Since the σ2 receptor has not been cloned, the current knowledge of this receptor has relied on receptor binding studies with the radiolabeled probes and investigation of the effects of the σ2 receptor ligands on tumor cells...
February 8, 2017: Handbook of Experimental Pharmacology
Joao Crispim, Wallace Chamon
According to the World Health Organization, cataract is the major cause of reversible visual impairment in the world. It is present as the cause of decreased visual acuity in 33% of the visual impaired citizens. With the increase of life expectancy in the last decades, the number of patients with cataract is expected to grow for the next 20 years. Nowadays, the only effective treatment for cataracts is surgery and its surgical outcomes have been increasingly satisfactory with the technological advancement...
February 8, 2017: Handbook of Experimental Pharmacology
Hiroko P Indo, Clare L Hawkins, Ikuo Nakanishi, Ken-Ichiro Matsumoto, Hirofumi Matsui, Shigeaki Suenaga, Michael J Davies, Daret K St Clair, Toshihiko Ozawa, Hideyuki J Majima
Mitochondria are a major source of intracellular energy and reactive oxygen species in cells, but are also increasingly being recognized as a controller of cell death. Here, we review evidence of signal transduction control by mitochondrial superoxide generation via the nuclear factor-κB (NF-κB) and GATA signaling pathways. We have also reviewed the effects of ROS on the activation of MMP and HIF. There is significant evidence to support the hypothesis that mitochondrial superoxide can initiate signaling pathways following transport into the cytosol...
February 8, 2017: Handbook of Experimental Pharmacology
Ulrike Taschler, Carina Hasenoehrl, Martin Storr, Rudolf Schicho
Cannabinoid receptors are fundamentally involved in all aspects of intestinal physiology, such as motility, secretion, and epithelial barrier function. They are part of a broader entity, the so-called endocannabinoid system which also includes their endocannabinoid ligands and the ligands' synthesizing/degrading enzymes. The system has a strong impact on the pathophysiology of the gastrointestinal tract and is believed to maintain homeostasis in the gut by controlling hypercontractility and by promoting regeneration after injury...
February 5, 2017: Handbook of Experimental Pharmacology
Andrea Strasser, Hans-Joachim Wittmann
Several experimental techniques to analyse histamine receptors are available, e.g. pharmacological characterisation of known or new compounds by different types of assays or mutagenesis studies. To obtain insights into the histamine receptors on a molecular and structural level, crystal structures have to be determined and molecular modelling studies have to be performed. It is widely accepted to generate homology models of the receptor of interest based on an appropriate crystal structure as a template and to refine the resulting models by molecular dynamic simulations...
January 22, 2017: Handbook of Experimental Pharmacology
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