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Multiple Pathways Mediate MicroRNA Degradation: Focus on the Translin/Trax RNase Complex.
Abstract The discovery of the microRNA system has revolutionized our understanding of translational control. Furthermore, growing appreciation of the pivotal role that de novo translation plays in activity-dependent synaptic plasticity has fueled interest among neuroscientists in deciphering how the microRNA system impacts neuronal signaling and the pathophysiology of neuropsychiatric disorders. Although we have a general understanding of how the microRNA system operates, many key questions remain. In particular, the biosynthesis of microRNAs and their role in translational silencing are fairly well understood. Ho...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Baraban JM, Shah A, Fu X Tags: Adv Pharmacol Source Type: research

Regulation of Mitochondrial, Cellular, and Organismal Functions by TSPO.
Abstract In 1999, the enigma of the 18kDa mitochondrial translocator protein (TSPO), also known as the peripheral-type benzodiazepine receptor, was the seeming disparity of the many functions attributed to TSPO, ranging from the potential of TSPO acting as a housekeeping gene at molecular biological levels to adaptations to stress, and even involvement in higher emotional and cognitive functioning, such as anxiety and depression. In the years since then, knowledge regarding the many functions modulated by TSPO has expanded, and understanding has deepened. In addition, new functions could be firmly associated with ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Gavish M, Veenman L Tags: Adv Pharmacol Source Type: research

Unique Effects of Clozapine: A Pharmacological Perspective.
Abstract Schizophrenia is a heterogenous and severe neuropsychiatric disorder that affects nearly 1% of the population worldwide. Antipsychotic drugs are the mainstay of treatment, but not all patients with schizophrenia respond to treatment with these agents. Clozapine, the first atypical antipsychotic, is a highly effective medication for patients with schizophrenia who do not respond to other antipsychotics. Although clozapine tends not to produce extrapyramidal symptoms, other side effects of the drug (e.g., agranulocytosis, myocarditis, seizures) limit its widespread use. This chapter reviews clozapine's uniq...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Khokhar JY, Henricks AM, Sullivan EDK, Green AI Tags: Adv Pharmacol Source Type: research

Imaging Translocator Protein as a Biomarker of Neuroinflammation in Dementia.
Abstract Neuroinflammation has long been considered a potential contributor to neurodegenerative disorders that result in dementia. Accumulation of abnormal protein aggregates in Alzheimer's disease, frontotemporal dementia, and dementia with Lewy bodies is associated with the activation of microglia and astrocytes into proinflammatory states, and chronic low-level activation of glial cells likely contributes to the pathological changes observed in these and other neurodegenerative diseases. The 18kDa translocator protein (TSPO) is a key biomarker for measuring inflammation in the brain via positron emission tomog...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Kreisl WC, Henter ID, Innis RB Tags: Adv Pharmacol Source Type: research

RNA-Based Fluorescent Biosensors for Detecting Metabolites in vitro and in Living Cells.
We describe the development of this new technology, its uses, and future directions to facilitate the use of this assay technology in mammalian cells and in high-throughput applications. PMID: 29413520 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Jaffrey SR Tags: Adv Pharmacol Source Type: research

Phosphorylation of the Amino Terminus of the Dopamine Transporter: Regulatory Mechanisms and Implications for Amphetamine Action.
Abstract Amphetamines (AMPHs) are potent psychostimulants that are widely used and abused, with profound medical and societal impact. Their actions at dopaminergic neurons are thought to mediate their therapeutic efficacy as well as their liability for abuse and dependence. AMPHs target the dopamine transporter (DAT), the plasmalemmal membrane protein that mediates the inactivation of released dopamine (DA) through its reuptake. AMPHs act as substrates for DAT and are known to cause mobilization of dopamine (DA) to the cell exterior via DAT-mediated reverse transport (efflux). It has become increasingly evident th...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Karam CS, Javitch JA Tags: Adv Pharmacol Source Type: research

Receptor Binding Assays and Drug Discovery.
Abstract Although Solomon Snyder authored hundreds of research reports and several books covering a broad range of topics in the neurosciences, he is best known by many as the person who developed neurotransmitter receptor radioligand binding assays. By demonstrating the utility of this approach for studying transmitter receptors in brain, Dr. Snyder provided the scientific community with a powerful new tool for identifying and characterizing these sites, for defining their relationship to neurological and psychiatric disorders, and their involvement in mediating the actions of psychotherapeutics. Although it was ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Bylund DB, Enna SJ Tags: Adv Pharmacol Source Type: research

Anti-NMDA Receptor Encephalitis: Clinical Features and Basic Mechanisms.
Abstract In slightly more than 10 years, anti-NMDA receptor (NMDAR) encephalitis has changed from a rare paraneoplastic syndrome to the most common cause of nonviral encephalitis. It presents fulminantly with progressive psychosis, seizures, and autonomic dysfunction, leading to death if untreated. However, rapid recognition and treatment can lead to survival and a return to baseline levels of functioning in many patients. While initially associated with ovarian teratomas, it is now associated with other tumors and can reflect a postviral event. The antibodies to the NMDAR made in this syndrome are pathogenic and ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Lynch DR, Rattelle A, Dong YN, Roslin K, Gleichman AJ, Panzer JA Tags: Adv Pharmacol Source Type: research

Mu Opioid Pharmacology: 40 Years to the Promised Land.
Abstract Opioids continue to play a major role in medicine, but not without problems. Side effects limit their utility medically, while the potential of addiction has had a major societal impact. Pharmacologists have been trying to develop opioids lacking side effects since the first derivative, heroin, was synthesized in the 1870s. The identification of opioid receptors about 40 years ago opened up new insights into our understanding of opioid action, fueled by the molecular biology revolution of the 1980s and 1990s. A major result of these studies was the discovery that the mu opioid receptor gene, Oprm1, underg...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Pasternak GW Tags: Adv Pharmacol Source Type: research

Synaptotoxic Signaling by Amyloid Beta Oligomers in Alzheimer's Disease Through Prion Protein and mGluR5.
Abstract Alzheimer's disease (AD) represents an impending global health crisis, yet the complexity of AD pathophysiology has so far precluded the development of any interventions to successfully slow or halt AD progression. It is clear that accumulation of Amyloid-beta (Aβ) peptide triggers progressive synapse loss to cause AD symptoms. Once initiated by Aβ, disease progression is complicated and accelerated by inflammation and by tau pathology. The recognition that Aβ peptide assumes multiple distinct states and that soluble oligomeric species (Aβo) are critical for synaptic damage is central ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Brody AH, Strittmatter SM Tags: Adv Pharmacol Source Type: research

The Neurobiology of d-Serine Signaling.
Abstract d-Serine is a physiological coagonist of NMDA receptors involved in synaptic plasticity, neurodevelopment, and neurodegeneration. d-Serine is synthesized by the enzyme serine racemase, which converts l- to d-serine. Recent studies indicate that the supply of l-serine by astroglia fuels the neuronal synthesis of d-serine. This pathway, named the serine shuttle, highlights the importance of the glia-neuron metabolic crosstalk for regulating NMDA receptor activity. Dysfunction of different components of the serine shuttle pathway leads to neurodevelopmental defects, neurodegeneration, and may be involved in ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Wolosker H Tags: Adv Pharmacol Source Type: research

The Role of Serine Racemase in the Pathophysiology of Brain Disorders.
Abstract The N-methyl-d-aspartate receptor (NMDAR) is unique in requiring two agonists to bind simultaneously to open its cation channel: the neurotransmitter, glutamate, and the coagonists, glycine, or d-serine. The Snyder laboratory was the first to clone serine racemase (SR), the enzyme that synthesizes d-serine, and to localize it immunocytochemically. Our laboratory has focused on the role of d-serine in brain disorders. Silencing the expression of SR, a risk gene for schizophrenia (SCZ), in mice (SR-/-), results in a phenotype that closely resembles SCZ including: cortical atrophy, reduced dendritic spine de...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Coyle JT, Balu DT Tags: Adv Pharmacol Source Type: research

Nitric Oxide Signaling in Neurodegeneration and Cell Death.
Abstract In this tribute to Solomon H. Snyder (Sol) we discuss the mechanisms by which nitric oxide (NO) kills neurons. We provide a historical perspective regarding the discovery that glutamate excitotoxicity is mediated by NO. It also contains a discussion of the discovery that neuronal nitric oxide synthase (nNOS) catalytic activity accounts for NADPH diaphorase activity and its localization in the central nervous system. NADPH diaphorase/nNOS neurons are unique in that they are resistant to toxic effects of excess glutamate and that they are resistant to neurodegeneration in a variety of neurodegenerative dise...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Dawson TM, Dawson VL Tags: Adv Pharmacol Source Type: research

Carboxypeptidase E and the Identification of Novel Neuropeptides as Potential Therapeutic Targets.
Abstract Peptides and small molecules that bind to peptide receptors are important classes of drugs that are used for a wide variety of different applications. The search for novel neuropeptides traditionally involved a time-consuming approach to purify each peptide to homogeneity and determine its amino acid sequence. The discovery in the 1980s of enkephalin convertase/carboxypeptidase E (CPE), and the observation that this enzyme was involved in the production of nearly every known neuropeptide led to the idea for a one-step affinity purification of CPE substrates. This approach was successfully used to isolate ...
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Fricker LD Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 29413530 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Pasternak GW, Coyle JT, Enna SJ Tags: Adv Pharmacol Source Type: research

Foreword.
PMID: 29413531 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 9, 2018 Category: Drugs & Pharmacology Authors: Iversen L Tags: Adv Pharmacol Source Type: research

The Dynamic Actin Cytoskeleton in Smooth Muscle.
Abstract Smooth muscle contraction requires both myosin activation and actin cytoskeletal remodeling. Actin cytoskeletal reorganization facilitates smooth muscle contraction by promoting force transmission between the contractile unit and the extracellular matrix (ECM), and by enhancing intercellular mechanical transduction. Myosin may be viewed to serve as an "engine" for smooth muscle contraction whereas the actin cytoskeleton may function as a "transmission system" in smooth muscle. The actin cytoskeleton in smooth muscle also undergoes restructuring upon activation with growth factors or th...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Tang DD Tags: Adv Pharmacol Source Type: research

Integrins in Vascular Development and Pathology.
Abstract During vascular development, endothelial cells (ECs) and neighboring stromal cells interact and communicate through autocrine and paracrine signaling mechanisms involving extracellular matrix (ECM) proteins and their cell surface integrin adhesion receptors. Integrin-mediated adhesion and signaling pathways are crucial for normal vascular development and physiology, and alterations in integrin expression and/or function drive several vascular-related pathologies including thrombosis, autoimmune disorders, and cancer. The purpose of this chapter is to discuss integrin adhesion and signaling pathways import...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Guerrero PA, McCarty JH Tags: Adv Pharmacol Source Type: research

Mechanotransduction in Blood and Lymphatic Vascular Development and Disease.
Abstract The blood and lymphatic vasculatures are hierarchical networks of vessels, which constantly transport fluids and, therefore, are exposed to a variety of mechanical forces. Considering the role of mechanotransduction is key for fully understanding how these vascular systems develop, function, and how vascular pathologies evolve. During embryonic development, for example, initiation of blood flow is essential for early vascular remodeling, and increased interstitial fluid pressure as well as initiation of lymph flow is needed for proper development and maturation of the lymphatic vasculature. In this review...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Urner S, Kelly-Goss M, Peirce SM, Lammert E Tags: Adv Pharmacol Source Type: research

Extracellular Matrix Macromolecules as Potential Targets of Cardiovascular Pharmacotherapy.
;inen H Abstract The extracellular matrix (ECM) forms the structural basis for the functional properties of different organs and tissues including the vasculature. Consequently, any alteration in the ECM may significantly influence the function of organs and tissues in question. This is also true for the cardiovascular system and its pathologies. Thus, therapies specifically targeting the ECM are likely very potent in the treatment of various diseases. Unfortunately, so far there are no therapies in clinical use primarily targeting the ECM. Nevertheless, most cardiovascular drugs are known to modulate the ECM and ...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Sainio A, Järveläinen H Tags: Adv Pharmacol Source Type: research

Matrix Metalloproteinases, Vascular Remodeling, and Vascular Disease.
Abstract Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that degrade various proteins in the extracellular matrix (ECM). Typically, MMPs have a propeptide sequence, a catalytic metalloproteinase domain with catalytic zinc, a hinge region or linker peptide, and a hemopexin domain. MMPs are commonly classified on the basis of their substrates and the organization of their structural domains into collagenases, gelatinases, stromelysins, matrilysins, membrane-type (MT)-MMPs, and other MMPs. MMPs are secreted by many cells including fibroblasts, vascular smooth muscle (VSM), and leukocyt...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Wang X, Khalil RA Tags: Adv Pharmacol Source Type: research

Mechanisms of I/R-Induced Endothelium-Dependent Vasodilator Dysfunction.
Abstract Ischemia/reperfusion (I/R) induces leukocyte/endothelial cell adhesive interactions (LECA) in postcapillary venules and impaired endothelium-dependent, NO-mediated dilatory responses (EDD) in upstream arterioles. A large body of evidence has implicated reactive oxygen species, adherent leukocytes, and proteases in postischemic EDD dysfunction in conduit arteries. However, arterioles represent the major site for the regulation of vascular resistance but have received less attention with regard to the mechanisms underlying their reduced responsiveness to EDD stimuli in I/R. Even though leukocytes do not rol...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Korthuis RJ Tags: Adv Pharmacol Source Type: research

The Role of Age-Related Intimal Remodeling and Stiffening in Atherosclerosis.
Abstract Age-related vascular stiffening is closely associated with cardiovascular risk. The clinical measure of arterial stiffness, pulse wave velocity, reflects bulk structural changes in the media observed with age, but does not reflect intimal remodeling that also drives atherosclerosis. Endothelial barrier integrity is disrupted during early atherogenesis and is regulated by the mechanics and composition of the underlying intima, which undergoes significant atherogenic remodeling in response to age and hemodynamics. Here, we first review the best characterized of these changes, including physiological intimal...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: VanderBurgh JA, Reinhart-King CA Tags: Adv Pharmacol Source Type: research

Smoothelins and the Control of Muscle Contractility.
Abstract Smooth muscle cells display distinctive expression and organization of contractile filament proteins, which reflect a unique method of contractile regulation. As the focus of this review, the smoothelin and smoothelin-like family members represent a family of poorly understood muscle proteins that appear to act as structural components of the contractile apparatus. The protein family is characterized by the presence a single C-terminal type-2 calponin homology (CH) domain. Often used as the preferred marker of differentiated contractile smooth muscle cells, smoothelin A and B (SMTN-A and SMTN-B) may influ...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Murali M, MacDonald JA Tags: Adv Pharmacol Source Type: research

The Cytoskeletal Network Regulates Expression of the Profibrotic Genes PAI-1 and CTGF in Vascular Smooth Muscle Cells.
Abstract Vascular smooth muscle cells (VSMCs) are subject to changing hemodynamic stimuli that alter cytoskeletal dynamics, cellular architecture, and structure-associated signal transduction. Tensional stress, force application, and structural perturbations are sensed by VSMCs and impact the physiological as well as pathophysiological responses of the vasculature. Microtubule-targeting drugs provide useful tools to analyze cytoskeletal-associated signaling pathways and their linkages to pathological outcomes. Architecture-based controls on a subset of profibrotic genes commonly expressed in vascular disease are h...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Samarakoon R, Higgins PJ Tags: Adv Pharmacol Source Type: research

Basic Components of Vascular Connective Tissue and Extracellular Matrix.
Abstract Though the composition of the three layers constituting the blood vessel wall varies among the different types of blood vessels, and some layers may even be missing in capillaries, certain basic components, and properties are shared by all blood vessels, though each histologically distinct layer contains a unique complement of extracellular components, growth factors and cytokines, and cell types as well. The structure and composition of vessel layers informs and is informed by the function of the particular blood vessel. The adaptation of the composition and the resulting function of the extracellular ma...
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Halper J Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 29310806 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - January 11, 2018 Category: Drugs & Pharmacology Authors: Khalil RA Tags: Adv Pharmacol Source Type: research

Endocannabinoid Analytical Methodologies: Techniques That Drive Discoveries That Drive Techniques.
Abstract Identification of the two major endogenous cannabinoid ligands, known as endocannabinoids, N-arachidonoyl-ethanolamine (anandamide, AEA) and 2-arachidonoyl-glycerol (2-AG), opened the way for the identification and isolation of other lipid congeners, all derivatives of fatty acids and related to the Endocannabinoid System. The nomenclature of this anandamide-type class of lipids is evolving as new species are discovered all the time. However, they each fall under the larger umbrella of lipids that are a conjugation of a fatty acid with an amine through and amide bond, which we will refer to as lipoamines....
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Piscitelli F, Bradshaw HB Tags: Adv Pharmacol Source Type: research

Spicing Up Pharmacology: A Review of Synthetic Cannabinoids From Structure to Adverse Events.
Abstract Recreational use of synthetic cannabinoids (SCB), a class of novel psychoactive substances is an increasing public health problem specifically in Western societies, with teenagers, young adults, and the prison population being the most affected. Some of these SCB are analogs of tetrahydrocannabinol, aminoalkylindoles, and other phytocannabinoid analogs have been detected in herbal preparations generically called "Spice." Spice, "K2" or "fake cannabis" is a general term used for variable herbal mixtures of unknown ingredients or chemical composition. SCB are highly potent CB1 ...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Davidson C, Opacka-Juffry J, Arevalo-Martin A, Garcia-Ovejero D, Molina-Holgado E, Molina-Holgado F Tags: Adv Pharmacol Source Type: research

CB1 and CB2 Receptor Pharmacology.
Abstract The CB1 and CB2 cannabinoid receptors (CB1R, CB2R) are members of the G protein-coupled receptor (GPCR) family that were identified over 20 years ago. CB1Rs and CB2Rs mediate the effects of Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the principal psychoactive constituent of marijuana, and subsequently identified endogenous cannabinoids (endocannabinoids) anandamide and 2-arachidonoyl glycerol. CB1Rs and CB2Rs have both similarities and differences in their pharmacology. Both receptors recognize multiple classes of agonist and antagonist compounds and produce an array of distinct downstream effects....
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Howlett AC, Abood ME Tags: Adv Pharmacol Source Type: research

Functional Selectivity at Cannabinoid Receptors.
Abstract It is now clear that, in contrast to traditional descriptions of G protein-coupled receptor signaling, agonists can activate or inhibit characteristic patterns of downstream effector pathways depending on their structures and the conformational changes induced in the receptor. This is referred to as functional selectivity (also known as agonist-directed trafficking, ligand-induced differential signaling, or biased agonism). It is important because even small structural differences can result in significant variations in overall agonist effects (wanted and unwanted) depending on which postreceptor signalin...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Priestley R, Glass M, Kendall D Tags: Adv Pharmacol Source Type: research

Cannabinoid Receptor-Related Orphan G Protein-Coupled Receptors.
Abstract Of the druggable group of G protein-coupled receptors in the human genome, a number remain which have yet to be paired with an endogenous ligand-orphan GPCRs. Among these 100 or so entities, 3 have been linked to the cannabinoid system. GPR18, GPR55, and GPR119 exhibit limited sequence homology with the established CB1 and CB2 cannabinoid receptors. However, the pharmacology of these orphan receptors displays overlap with CB1 and CB2 receptors, particularly for GPR18 and GPR55. The linking of GPR119 to the cannabinoid receptors is less convincing and emanates from structural similarities of endogenous lig...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Irving A, Abdulrazzaq G, Chan SLF, Penman J, Harvey J, Alexander SPH Tags: Adv Pharmacol Source Type: research

Actions and Regulation of Ionotropic Cannabinoid Receptors.
Abstract Almost three decades have passed since the identification of the two specific metabotropic receptors mediating cannabinoid pharmacology. Thereafter, many cannabinoid effects, both at central and peripheral levels, have been well documented and characterized. However, numerous evidences demonstrated that these pharmacological actions could not be attributable solely to the activation of CB1 and CB2 receptors since several important cannabimimetic actions have been found in biological systems lacking CB1 or CB2 gene such as in specific cell lines or transgenic mice. It is now well accepted that, beyond thei...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: De Petrocellis L, Nabissi M, Santoni G, Ligresti A Tags: Adv Pharmacol Source Type: research

The Role of Nuclear Hormone Receptors in Cannabinoid Function.
Abstract Since the early 2000s, evidence has been accumulating that most cannabinoid compounds interact with the nuclear hormone family peroxisome proliferator-activated receptors (PPARs). This can be through direct binding of these compounds to PPARs, metabolism of cannabinoid to other PPAR-activating chemicals, or indirect activation of PPAR through cell signaling pathways. Delivery of cannabinoids to the nucleus may be facilitated by fatty acid-binding proteins and carrier proteins. All PPAR isoforms appear to be activated by cannabinoids, but the majority of evidence is for PPARα and γ. To date, li...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Pistis M, O'Sullivan SE Tags: Adv Pharmacol Source Type: research

Endocannabinoid Turnover.
We describe the enzymes associated with these events and their characterization. We identify the inhibitor profile for these enzymes and the status of therapeutic exploitation, which to date has been limited to clinical trials for fatty acid amide hydrolase inhibitors. To bring the review to a close, we consider whether point block of a single enzyme is likely to be the most successful approach for therapeutic exploitation of the endocannabinoid system. PMID: 28826539 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Fowler CJ, Doherty P, Alexander SPH Tags: Adv Pharmacol Source Type: research

Cannabinoids in the Cardiovascular System.
Abstract Cannabinoids are known to modulate cardiovascular functions including heart rate, vascular tone, and blood pressure in humans and animal models. Essential components of the endocannabinoid system, namely, the production, degradation, and signaling pathways of endocannabinoids have been described not only in the central and peripheral nervous system but also in myocardium, vasculature, platelets, and immune cells. The mechanisms of cardiovascular responses to endocannabinoids are often complex and may involve cannabinoid CB1 and CB2 receptors or non-CB1/2 receptor targets. Preclinical and some clinical stu...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Ho WSV, Kelly MEM Tags: Adv Pharmacol Source Type: research

Is the Cannabinoid CB2 Receptor a Major Regulator of the Neuroinflammatory Axis of the Neurovascular Unit in Humans?
Abstract The central nervous system (CNS) is an immune privileged site where the neurovascular unit (NVU) and the blood-brain barrier (BBB) act as a selectively permeable interface to control the passage of nutrients and inflammatory cells into the brain parenchyma. However, in response to injury, infection, or disease, CNS cells become activated, and release inflammatory mediators to recruit immune cells to the site of inflammation. Increasing evidence suggests that cannabinoids may have a neuroprotective role in CNS inflammatory conditions. For many years, it was widely accepted that cannabinoid receptor type 1 ...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Kho DT, Glass M, Graham ES Tags: Adv Pharmacol Source Type: research

Cannabinoids as Anticancer Drugs.
Abstract The endocannabinoid system encompassing cannabinoid receptors, endogenous receptor ligands (endocannabinoids), as well as enzymes conferring the synthesis and degradation of endocannabinoids has emerged as a considerable target for pharmacotherapeutical approaches of numerous diseases. Besides palliative effects of cannabinoids used in cancer treatment, phytocannabinoids, synthetic agonists, as well as substances that increase endogenous endocannabinoid levels have gained interest as potential agents for systemic cancer treatment. Accordingly, cannabinoid compounds have been reported to inhibit tumor grow...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Ramer R, Hinz B Tags: Adv Pharmacol Source Type: research

Cannabinoids and Pain: Sites and Mechanisms of Action.
Abstract The endocannabinoid system, consisting of the cannabinoid1 receptor (CB1R) and cannabinoid2 receptor (CB2R), endogenous cannabinoid ligands (endocannabinoids), and metabolizing enzymes, is present throughout the pain pathways. Endocannabinoids, phytocannabinoids, and synthetic cannabinoid receptor agonists have antinociceptive effects in animal models of acute, inflammatory, and neuropathic pain. CB1R and CB2R located at peripheral, spinal, or supraspinal sites are important targets mediating these antinociceptive effects. The mechanisms underlying the analgesic effects of cannabinoids likely include inhi...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Starowicz K, Finn DP Tags: Adv Pharmacol Source Type: research

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.
Abstract The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational co...
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Russo EB, Marcu J Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 28826545 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - August 23, 2017 Category: Drugs & Pharmacology Authors: Kendall D, Alexander SPH Tags: Adv Pharmacol Source Type: research

GABAA Receptors and the Diversity in their Structure and Pharmacology.
Abstract GABAA receptors (GABAARs) are a class of ligand-gated ion channels with high physiological and therapeutic significance. In the brain, these pentameric receptors occur with diverse subunit composition, which confers highly complex pharmacology to this receptor class. An impressive range of clinically used therapeutics are known to bind to distinct sites found on GABAARs to modulate receptor function. Numerous experimental approaches have been used over the years to elucidate the binding sites of these drugs, but unequivocal identification is challenging due to subtype- and ligand-dependent pharmacology. H...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Chua HC, Chebib M Tags: Adv Pharmacol Source Type: research

Role of Nonneuronal TRPV4 Signaling in Inflammatory Processes.
Abstract Transient receptor potential (TRP) ion channels are important signaling components in nociceptive and inflammatory pathways. This is attributed to their ability to function as polymodal sensors of environmental stimuli (chemical and mechanical) and as effector molecules in receptor signaling pathways. TRP vanilloid 4 (TRPV4) is a nonselective cation channel that is activated by multiple endogenous stimuli including shear stress, membrane stretch, and arachidonic acid metabolites. TRPV4 contributes to many important physiological processes and dysregulation of its activity is associated with chronic condit...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Rajasekhar P, Poole DP, Veldhuis NA Tags: Adv Pharmacol Source Type: research

Genetically Encoded Calcium Indicators as Probes to Assess the Role of Calcium Channels in Disease and for High-Throughput Drug Discovery.
Abstract The calcium ion (Ca(2+)) is an important signaling molecule implicated in many cellular processes, and the remodeling of Ca(2+) homeostasis is a feature of a variety of pathologies. Typical methods to assess Ca(2+) signaling in cells often employ small molecule fluorescent dyes, which are sometimes poorly suited to certain applications such as assessment of cellular processes, which occur over long periods (hours or days) or in vivo experiments. Genetically encoded calcium indicators are a set of tools available for the measurement of Ca(2+) changes in the cytosol and subcellular compartments, which circu...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Bassett JJ, Monteith GR Tags: Adv Pharmacol Source Type: research

TRPV1 Channels in Immune Cells and Hematological Malignancies.
Abstract Transient receptor potential vanilloid-1 (TRPV1) is a member of the TRP family of channels that are responsible for nociceptive, thermal, and mechanical sensations. Originally associated exclusively with sensory neurons, TRPV1 is now known to be present in almost all organs, including cells of the immune system, where TRPV1 has been shown to play a pivotal role in inflammation and immunity. Monocytes, macrophages, and dendritic cells express TRPV1, with both mouse and human studies suggesting that TRPV1 activation protects against endotoxin-induced inflammation. In contrast, TRPV1 (and other TRP channels)...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Omari SA, Adams MJ, Geraghty DP Tags: Adv Pharmacol Source Type: research

Modulation of Ion Channels by Cysteine-Rich Peptides: From Sequence to Structure.
Abstract Venom peptides are natural ligands of ion channels and have been used extensively in pharmacological characterization of various ion channels and receptors. In this chapter, we survey all known venom peptide ion-channel modulators. Our survey reveals that the majority of venom peptides characterized to date target voltage-gated sodium or potassium channels. We further find that the majority of these peptides are found in scorpion and spider venoms. We discuss the influence of the pharmacological tools available in biasing discovery and the classical "toxin-to-sequence" approach to venom peptide ...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Mobli M, Undheim EAB, Rash LD Tags: Adv Pharmacol Source Type: research

Glycine Receptor Drug Discovery.
Abstract Postsynaptic glycine receptor (GlyR) chloride channels mediate inhibitory neurotransmission in the spinal cord and brain stem, although presynaptic and extrasynaptic GlyRs are expressed more widely throughout the brain. In humans, GlyRs are assembled as homo- or heteromeric pentamers of α1-3 and β subunits. GlyR malfunctions have been linked to a range of neurological disorders including hyperekplexia, temporal lobe epilepsy, autism, breathing disorders, and chronic inflammatory pain. Although it is possible that GlyRs may eventually be clinically targeted for a variety of neurological disorder...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Lynch JW, Zhang Y, Talwar S, Estrada-Mondragon A Tags: Adv Pharmacol Source Type: research

Voltage-Gated Sodium Channel Pharmacology: Insights From Molecular Dynamics Simulations.
Abstract Voltage-gated ion channels are the target of a range of naturally occurring toxins and therapeutic drugs. There is a great interest in better understanding how these diverse compounds alter channel function in order to design the next generation of therapeutics that can selectively target one of the channel subtypes found in the body. Since the publication of a number of bacterial sodium channel structures, molecular dynamics simulations have been invaluable in gaining a high resolution understanding where many of these small molecules and toxins bind to the channels, how they find their binding site, and...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Chen R, Buyan A, Corry B Tags: Adv Pharmacol Source Type: research

Physiology and Pharmacology of Ryanodine Receptor Calcium Release Channels.
Abstract Ryanodine receptor (RyR) ion channels are essential for skeletal and cardiac muscle function. Their knockout leads to perinatal death from respiratory and cardiac failure. Acquired changes or mutations in the protein cause debilitating skeletal myopathy and cardiac arrhythmia which can be deadly. Knowledge of the pharmacology of RyR channels is central to developing effective and specific treatments of these myopathies. The ion channel is a>2.2MDa homotetamer with distinct structural and functional characteristics giving rise to a myriad of regulatory sites that are potential therapeutic targets. Austr...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Dulhunty AF, Board PG, Beard NA, Casarotto MG Tags: Adv Pharmacol Source Type: research

Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future ….
Acid-Sensing Ion Channel Pharmacology, Past, Present, and Future …. Adv Pharmacol. 2017;79:35-66 Authors: Rash LD Abstract pH is one of the most strictly controlled parameters in mammalian physiology. An extracellular pH of ~7.4 is crucial for normal physiological processes, and perturbations to this have profound effects on cell function. Acidic microenvironments occur in many physiological and pathological conditions, including inflammation, bone remodeling, ischemia, trauma, and intense synaptic activity. Cells exposed to these conditions respond in different ways, from tumor cells that thri...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Rash LD Tags: Adv Pharmacol Source Type: research