Sodium Channels and Venom Peptide Pharmacology.
Abstract Venomous animals including cone snails, spiders, scorpions, anemones, and snakes have evolved a myriad of components in their venoms that target the opening and/or closing of voltage-gated sodium channels to cause devastating effects on the neuromuscular systems of predators and prey. These venom peptides, through design and serendipity, have not only contributed significantly to our understanding of sodium channel pharmacology and structure, but they also represent some of the most phyla- and isoform-selective molecules that are useful as valuable tool compounds and drug leads. Here, we review our unders...
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Israel MR, Tay B, Deuis JR, Vetter I Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 28528675 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - May 24, 2017 Category: Drugs & Pharmacology Authors: Geraghty DP, Rash LD Tags: Adv Pharmacol Source Type: research

Nanojunctions of the Sarcoplasmic Reticulum Deliver Site- and Function-Specific Calcium Signaling in Vascular Smooth Muscles.
Abstract Vasoactive agents may induce myocyte contraction, dilation, and the switch from a contractile to a migratory-proliferative phenotype(s), which requires changes in gene expression. These processes are directed, in part, by Ca(2+) signals, but how different Ca(2+) signals are generated to select each function is enigmatic. We have previously proposed that the strategic positioning of Ca(2+) pumps and release channels at membrane-membrane junctions of the sarcoplasmic reticulum (SR) demarcates cytoplasmic nanodomains, within which site- and function-specific Ca(2+) signals arise. This chapter will describe h...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Evans AM Tags: Adv Pharmacol Source Type: research

Sodium-Calcium Exchanger in Pig Coronary Artery.
Abstract This review focuses on the sodium-calcium exchangers (NCX) in the left anterior descending coronary artery smooth muscle. Bathing tissues in Na(+)-substituted solutions caused them to contract. In cultured smooth muscle cells, it increased the cytosolic Ca(2+) concentration and extracellular entry of (45)Ca(2+). All three activities were attributed to NCX since they were inhibited by NCX inhibitors. The tissues also expressed the sarco/endoplasmic reticulum (SER) Ca(2+) pump SERCA2b whose activity was much greater than that of NCX. Inhibiting SERCA2b with thapsigargin decreased the NCX-mediated (45)Ca(2+)...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Grover AK Tags: Adv Pharmacol Source Type: research

Ca(2+)/Calmodulin-Dependent Protein Kinase II in Vascular Smooth Muscle.
Abstract Ca(2+)-dependent signaling pathways are central regulators of differentiated vascular smooth muscle (VSM) contractile function. In addition, Ca(2+) signals regulate VSM gene transcription, proliferation, and migration of dedifferentiated or "synthetic" phenotype VSM cells. Synthetic phenotype VSM growth and hyperplasia are hallmarks of pervasive vascular diseases including hypertension, atherosclerosis, postangioplasty/in-stent restenosis, and vein graft failure. The serine/threonine protein kinase Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a ubiquitous mediator of intracellular C...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Saddouk FZ, Ginnan R, Singer HA Tags: Adv Pharmacol Source Type: research

Protein Kinase C as Regulator of Vascular Smooth Muscle Function and Potential Target in Vascular Disorders.
Abstract Vascular smooth muscle (VSM) plays an important role in maintaining vascular tone. In addition to Ca(2+)-dependent myosin light chain (MLC) phosphorylation, protein kinase C (PKC) is a major regulator of VSM function. PKC is a family of conventional Ca(2+)-dependent α, β, and γ, novel Ca(2+)-independent δ, ɛ, θ, and η, and atypical ξ, and ι/λ isoforms. Inactive PKC is mainly cytosolic, and upon activation it undergoes phosphorylation, maturation, and translocation to the surface membrane, the nucleus, endoplasmic reticulum, and other cell organelles; a proc...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Ringvold HC, Khalil RA Tags: Adv Pharmacol Source Type: research

Rho-Mancing to Sensitize Calcium Signaling for Contraction in the Vasculature: Role of Rho Kinase.
Abstract Vascular smooth muscle contraction is an important physiological process contributing to cardiovascular homeostasis. The principal determinant of smooth muscle contraction is the intracellular free Ca(2+) concentration, and phosphorylation of myosin light chain (MLC) by activated myosin light chain kinase (MLCK) in response to increased Ca(2+) is the main pathway by which vasoconstrictor stimuli induce crossbridge cycling of myosin and actin filaments. A secondary pathway for vascular smooth muscle contraction that is not directly dependent on Ca(2+) concentration, but rather mediating Ca(2+) sensitizatio...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Szasz T, Webb RC Tags: Adv Pharmacol Source Type: research

Vascular Cells in Blood Vessel Wall Development and Disease.
Abstract The vessel wall is composed of distinct cellular layers, yet communication among individual cells within and between layers results in a dynamic and versatile structure. The morphogenesis of the normal vascular wall involves a highly regulated process of cell proliferation, migration, and differentiation. The use of modern developmental biological and genetic approaches has markedly enriched our understanding of the molecular and cellular mechanisms underlying these developmental events. Additionally, the application of similar approaches to study diverse vascular diseases has resulted in paradigm-shiftin...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Mazurek R, Dave JM, Chandran RR, Misra A, Sheikh AQ, Greif DM Tags: Adv Pharmacol Source Type: research

Notch Signaling in Vascular Smooth Muscle Cells.
Abstract The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical in...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Baeten JT, Lilly B Tags: Adv Pharmacol Source Type: research

Smooth Muscle Phenotypic Diversity: Effect on Vascular Function and Drug Responses.
Abstract At its simplest resistance to blood flow is regulated by changes in the state of contraction of the vascular smooth muscle (VSM), a function of the competing activities of the myosin kinase and phosphatase determining the phosphorylation and activity of the myosin ATPase motor protein. In contrast, the vascular system of humans and other mammals is incredibly complex and highly regulated. Much of this complexity derives from phenotypic diversity within the smooth muscle, reflected in very differing power outputs and responses to signaling pathways that regulate vessel tone, presumably having evolved over ...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Fisher SA Tags: Adv Pharmacol Source Type: research

Calcium Channels in Vascular Smooth Muscle.
do MF Abstract Calcium (Ca(2+)) plays a central role in excitation, contraction, transcription, and proliferation of vascular smooth muscle cells (VSMs). Precise regulation of intracellular Ca(2+) concentration ([Ca(2+)]i) is crucial for proper physiological VSM function. Studies over the last several decades have revealed that VSMs express a variety of Ca(2+)-permeable channels that orchestrate a dynamic, yet finely tuned regulation of [Ca(2+)]i. In this review, we discuss the major Ca(2+)-permeable channels expressed in VSM and their contribution to vascular physiology and pathology. PMID: 28212803 [PubMed ...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Ghosh D, Syed AU, Prada MP, Nystoriak MA, Santana LF, Nieves-Cintrón M, Navedo MF Tags: Adv Pharmacol Source Type: research

Potassium Channels in Regulation of Vascular Smooth Muscle Contraction and Growth.
Abstract Potassium channels importantly contribute to the regulation of vascular smooth muscle (VSM) contraction and growth. They are the dominant ion conductance of the VSM cell membrane and importantly determine and regulate membrane potential. Membrane potential, in turn, regulates the open-state probability of voltage-gated Ca(2+) channels (VGCC), Ca(2+) influx through VGCC, intracellular Ca(2+), and VSM contraction. Membrane potential also affects release of Ca(2+) from internal stores and the Ca(2+) sensitivity of the contractile machinery such that K(+) channels participate in all aspects of regulation of V...
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Jackson WF Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 28212805 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - February 20, 2017 Category: Drugs & Pharmacology Authors: Khalil RA Tags: Adv Pharmacol Source Type: research

The Endothelium-Dependent Nitric Oxide-cGMP Pathway.
In conclusion, the discovery of the NO-cGMP pathway revolutionized the comprehension of pathophysiological mechanisms involved in cardiovascular and other diseases. However, considering the expression "from bench to bedside" the therapeutic alternatives targeting NO-cGMP did not immediately follow the marked biochemical and pathophysiological revolution. Some therapeutic options have been effective and released on the market for pulmonary hypertension and erectile dysfunction such as inhaled NO, PDE5 inhibitors, and recently sGC stimulators. The therapeutic armamentarium for many other disorders is expected in th...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Mónica FZ, Bian K, Murad F Tags: Adv Pharmacol Source Type: research

Transcriptional and Posttranslational Regulation of eNOS in the Endothelium.
Abstract Nitric oxide (NO) is a highly reactive free radical gas and these unique properties have been adapted for a surprising number of biological roles. In neurons, NO functions as a neurotransmitter; in immune cells, NO contributes to host defense; and in endothelial cells, NO is a major regulator of blood vessel homeostasis. In the vasculature, NO is synthesized on demand by a specific enzyme, endothelial nitric oxide synthase (eNOS) that is uniquely expressed in the endothelial cells that form the interface between the circulating blood and the various tissues of the body. NO regulates endothelial and blood ...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Fulton DJ Tags: Adv Pharmacol Source Type: research

Endothelial Small- and Intermediate-Conductance K Channels and Endothelium-Dependent Hyperpolarization as Drug Targets in Cardiovascular Disease.
, Wulff H Abstract Endothelial calcium/calmodulin-gated K channels of small (KCa2.3) and intermediate conductance (KCa3.1) produce membrane hyperpolarization and endothelium-dependent hyperpolarization (EDH)-mediated vasodilation. Dysfunctions of the two channels and ensuing EDH impairments are found in several cardiovascular pathologies such as diabetes, atherosclerosis, postangioplastic neointima formation, but also inflammatory disease, cancer, and organ fibrosis. Moreover, KCa3.1 plays an important role in endothelial barrier dysfunction, edema formation in cardiac and pulmonary disease, and in ischemic stroke...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Köhler R, Oliván-Viguera A, Wulff H Tags: Adv Pharmacol Source Type: research

Epoxyeicosatrienoic Acids and 20-Hydroxyeicosatetraenoic Acid on Endothelial and Vascular Function.
The objective of this review is to focus on the physiology and pharmacology of endothelial CYP metabolites. The CYP pathway produces two types of eicosanoid products: epoxyeicosatrienoic acids (EETs), formed by CYP epoxygenases, and hydroxyeicosatetraenoic acids (HETEs), formed by CYP hydroxylases. Advances in CYP enzymes, EETs, and 20-HETE by pharmacological and genetic means have led to a more complete understanding of how these eicosanoids impact on endothelial cell function. Endothelial-derived EETs were initially described as endothelial-derived hyperpolarizing factors. It is now well recognized that EETs importantly ...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Imig JD Tags: Adv Pharmacol Source Type: research

Endothelin-1: Biosynthesis, Signaling and Vasoreactivity.
ste P Abstract Endothelin-1 (ET-1) is an extremely potent vasoconstrictor peptide originally isolated from endothelial cells. Its synthesis, mainly regulated at the gene transcription level, involves processing of a precursor by a furin-type proprotein convertase to an inactive intermediate, big ET-1. The latter peptide can then be cleaved directly by an endothelin-converting enzyme (ECE) into ET-1 or reach the active metabolite through a two-step process involving chymase hydrolyzing big ET-1 to ET-1 (1-31), itself needing conversion to ET-1 by neprilysin (NEP) to exert physiological activity. ET-1 signals throug...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Houde M, Desbiens L, D'Orléans-Juste P Tags: Adv Pharmacol Source Type: research

Endothelium-Dependent Contractions: Prostacyclin and Endothelin-1, Partners in Crime?
Abstract Both the lipid prostacyclin and the peptide endothelin-1 are endothelium-derived substances. Endothelin-1 is one of the most powerful endogenous vasoconstrictors, while prostacyclin is a potent antiaggregatory and vasodilator mediator upon activation of prostaglandin I2 (IP) receptors. During endothelium-dependent, prostanoid-mediated contractions/constrictions, however, prostacyclin appears to be a major endothelium-derived contracting factor (EDCF). Such cyclooxygenase-dependent responses, whether measured ex vivo or in vivo, are exacerbated by aging, obesity, diabetes, or hypertension. On the backgroun...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Baretella O, Vanhoutte PM Tags: Adv Pharmacol Source Type: research

Communication Through Gap Junctions in the Endothelium.
Abstract A swarm of fish displays a collective behavior (swarm behavior) and moves "en masse" despite the huge number of individual animals. In analogy, organ function is supported by a huge number of cells that act in an orchestrated fashion and this applies also to vascular cells along the vessel length. It is obvious that communication is required to achieve this vital goal. Gap junctions with their modular bricks, connexins (Cxs), provide channels that interlink the cytosol of adjacent cells by a pore sealed against the extracellular space. This allows the transfer of ions and charge and thereby the ...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Schmidt K, Windler R, de Wit C Tags: Adv Pharmacol Source Type: research

Molecular Signaling Pathways Controlling Vascular Tube Morphogenesis and Pericyte-Induced Tube Maturation in 3D Extracellular Matrices.
Abstract During capillary network formation, ECs establish interconnecting tubes with defined lumens that reside within vascular guidance tunnels (physical spaces generated during EC tubulogenesis). Pericytes are recruited to EC tubes within these tunnels and capillary basement membrane deposition occurs to facilitate tube maturation. Here, we discuss molecular mechanisms controlling EC tubulogenesis demonstrating the involvement of integrins, MT1-MMP, extracellular matrix, Cdc42, Rac1, Rac2, k-Ras, Rap1b, and key downstream effectors including Pak2, Pak4, IQGAP1, MRCKβ, and Rasip1. These molecules activate k...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Bowers SL, Norden PR, Davis GE Tags: Adv Pharmacol Source Type: research

Stress-Induced Premature Senescence of Endothelial and Endothelial Progenitor Cells.
Abstract This brief overview of premature senescence of dysfunctional endothelial and endothelial progenitor cells provides information on endothelial cell differentiation and specialization, their ontogeny, and controversies related to endothelial stem and progenitor cells. Stressors responsible for the dysfunction of endothelial and endothelial progenitor cells, as well as cellular mechanisms and consequences of endothelial cell dysfunction are presented. Metabolic signatures of dysfunctional endothelial cells and senescence pathways are described. Emerging strategies to rejuvenate endothelial and endothelial pr...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Goligorsky MS, Hirschi K Tags: Adv Pharmacol Source Type: research

Estrogens and Coronary Artery Disease: New Clinical Perspectives.
Abstract In premenopausal women, endogenous estrogens are associated with reduced prevalence of arterial hypertension, coronary artery disease, myocardial infarction, and stroke. Clinical trials conducted in the 1990s such as HERS, WHI, and WISDOM have shown that postmenopausal treatment with horse hormone mixtures (so-called conjugated equine estrogens) and synthetic progestins adversely affects female cardiovascular health. Our understanding of rapid (nongenomic) and chronic (genomic) estrogen signaling has since advanced considerably, including identification of a new G protein-coupled estrogen receptor (GPER),...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Meyer MR, Barton M Tags: Adv Pharmacol Source Type: research

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia.
Abstract Preeclampsia is a pregnancy-related disorder characterized by hypertension and could lead to maternal and fetal morbidity and mortality. Although the causative factors and pathophysiological mechanisms are unclear, endothelial dysfunction is a major hallmark of preeclampsia. Clinical tests and experimental research have suggested that generalized endotheliosis in the systemic, renal, cerebral, and hepatic circulation could decrease endothelium-derived vasodilators such as nitric oxide, prostacyclin, and hyperpolarization factor and increase vasoconstrictors such as endothelin-1 and thromboxane A2, leading...
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Possomato-Vieira JS, Khalil RA Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 27451104 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - July 29, 2016 Category: Drugs & Pharmacology Authors: Khalil RA Tags: Adv Pharmacol Source Type: research

My Life in Clinical Neuroscience: The Beginning.
Abstract This chapter recounts the author's life from childhood until he opened his research laboratory as an Assistant Professor in the Department of Pharmacology and Experimental Therapeutics at Johns Hopkins School of Medicine in 1976. It emphasizes the importance of chance opportunities and generous mentoring in the initiation of his career in neuroscience and psychiatric research. PMID: 27288071 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Coyle JT Tags: Adv Pharmacol Source Type: research

Kynurenines and Glutamate: Multiple Links and Therapeutic Implications.
Abstract Glutamate is firmly established as the major excitatory neurotransmitter in the mammalian brain and is actively involved in most aspects of neurophysiology. Moreover, glutamatergic impairments are associated with a wide variety of dysfunctional states, and both hypo- and hyperfunction of glutamate have been plausibly linked to the pathophysiology of neurological and psychiatric diseases. Metabolites of the kynurenine pathway (KP), the major catabolic route of the essential amino acid tryptophan, influence glutamatergic activity in several distinct ways. This includes direct effects of these "kynureni...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Schwarcz R Tags: Adv Pharmacol Source Type: research

The Therapeutic Role of d-Cycloserine in Schizophrenia.
Abstract The ketamine model for schizophrenia has led to several therapeutic strategies for enhancing N-methyl d-aspartate (NMDA) receptor activity, including agonists directed at the glycine receptor site and inhibitors of glycine reuptake. Because ketamine may primarily block NMDA receptors on inhibitory interneurons, drugs that reduce glutamate release have also been investigated as a means of countering a deficit in inhibitory input. These approaches have met with some success for the treatment of negative and positive symptoms, but results have not been consistent. An emerging approach with the NMDA partial a...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Goff D Tags: Adv Pharmacol Source Type: research

Impulsivity, Stimulant Abuse, and Dopamine Receptor Signaling.
Abstract The nonmedical use of amphetamine-type stimulants is a worldwide problem, with substantial medical and social consequences. Nonetheless, the identification of a pharmacological treatment for amphetamine use disorder remains elusive. Stimulant users exhibit neurochemical evidence of dopamine-system dysfunction as well as impulsive behaviors that may interfere with the success of treatments for their addiction. This review focuses on the potential role of dopaminergic neurotransmission in impulsivity, both in healthy individuals and chronic stimulant users who meet criteria for methamphetamine dependence. P...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: London ED Tags: Adv Pharmacol Source Type: research

Excitotoxicity as a Common Mechanism for Fetal Neuronal Injury with Hypoxia and Intrauterine Inflammation.
Abstract Excitotoxicity is a mechanism of neuronal injury, implicated in the pathogenesis of many acute and chronic neurologic disorders, including perinatal brain injury associated with hypoxia-ischemia and exposure to intrauterine inflammation. Glutamate, the primary excitatory neurotransmitter, signals through N-methyl-d-aspartic acid (NMDA)/α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. Proper functioning of both of these receptors, in conjunction with glutamate signaling, is crucial for normal development. However, even a small imbalance can result in perinatal neuronal injury. There...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Burd I, Welling J, Kannan G, Johnston MV Tags: Adv Pharmacol Source Type: research

Transcriptional Regulation of Glutamate Transporters: From Extracellular Signals to Transcription Factors.
Abstract Glutamate is the predominant excitatory neurotransmitter in the mammalian CNS. It mediates essentially all rapid excitatory signaling. Dysfunction of glutamatergic signaling contributes to developmental, neurologic, and psychiatric diseases. Extracellular glutamate is cleared by a family of five Na(+)-dependent glutamate transporters. Two of these transporters (GLAST and GLT-1) are relatively selectively expressed in astrocytes. Other of these transporters (EAAC1) is expressed by neurons throughout the nervous system. Expression of the last two members of this family (EAAT4 and EAAT5) is almost exclusivel...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Martinez-Lozada Z, Guillem AM, Robinson MB Tags: Adv Pharmacol Source Type: research

The Long and Winding Road: From the High-Affinity Choline Uptake Site to Clinical Trials for Malignant Brain Tumors.
Abstract Malignant brain tumors are one of the most lethal cancers. They originate from glial cells which infiltrate throughout the brain. Current standard of care involves surgical resection, radiotherapy, and chemotherapy; median survival is currently ~14-20 months postdiagnosis. Given that the brain immune system is deficient in priming systemic immune responses to glioma antigens, we proposed to reconstitute the brain immune system to achieve immunological priming from within the brain. Two adenoviral vectors are injected into the resection cavity or remaining tumor. One adenoviral vector expresses the HSV-1-d...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Lowenstein PR, Castro MG Tags: Adv Pharmacol Source Type: research

Choline on the Move: Perspectives on the Molecular Physiology and Pharmacology of the Presynaptic Choline Transporter.
Abstract Genetic, biochemical, physiological, and pharmacological approaches have advanced our understanding of cholinergic biology for over 100 years. High-affinity choline uptake (HACU) was one of the last features of cholinergic signaling to be defined at a molecular level, achieved through the cloning of the choline transporter (CHT, SLC5A7). In retrospect, the molecular era of CHT studies initiated with the identification of hemicholinium-3 (HC-3), a potent, competitive CHT antagonist, though it would take another 30 years before HC-3, in radiolabeled form, was used by Joseph Coyle's laboratory to identify an...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Ennis EA, Blakely RD Tags: Adv Pharmacol Source Type: research

Still NAAG'ing After All These Years: The Continuing Pursuit of GCPII Inhibitors.
Abstract Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca(2+)-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was pu...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Vornov JJ, Hollinger KR, Jackson PF, Wozniak KM, Farah MH, Majer P, Rais R, Slusher BS Tags: Adv Pharmacol Source Type: research

Ultimate Translation: Developing Therapeutics Targeting on N-Methyl-d-Aspartate Receptor.
Abstract N-Methyl-d-aspartate receptors (NMDARs) are broadly distributed in the central nervous system (CNS), where they mediate excitatory signaling. NMDAR-mediated neurotransmission (NMDARMN) is the molecular engine of learning, memory and cognition, which are the basis for high cortical function. NMDARMN is also critically involved in the development and plasticity of CNS. Due to its essential and critical role, either over- or under-activation of NMDARMN can contribute substantially to the development of CNS disorders. The involvement of NMDARMN has been demonstrated in a variety of CNS disorders, including sc...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Tsai GE Tags: Adv Pharmacol Source Type: research

The Good and Bad Sides of NAAG.
Abstract Why has such a small peptide been the source of controversy in neuroscience over the last 5 decades? Is N-acetyl-aspartyl-glutamate (NAAG) a neurotransmitter? Is NAAG located in neuronal tissue or in astrocytes? Is NAAG involved in neuropsychiatric and neurodegenerative disorders? Is NAAG therapeutically beneficial in the treatment of stroke or in initiating cascades of events leading to psychosis? After many years of intense research there is no clear consensus within the scientific community on how NAAG behaves in the brain. One of the major controversies about NAAG is its physiological action at N-meth...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Khacho P, Wang B, Bergeron R Tags: Adv Pharmacol Source Type: research

The NMDA Receptor and Schizophrenia: From Pathophysiology to Treatment.
Abstract Schizophrenia is a severe mental illness that affects almost 1% of the population worldwide. Even though the etiology of schizophrenia is uncertain, it is believed to be a neurodevelopmental disorder that results from a combination of environmental insults and genetic vulnerabilities. Over the past 20 years, there has been a confluence of evidence from many research disciplines pointing to alterations in excitatory signaling, particularly involving hypofunction of the N-methyl-d-aspartate receptor (NMDAR), as a key contributor to the schizophrenia disease process. This review describes the structure-funct...
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Balu DT Tags: Adv Pharmacol Source Type: research

Foreword.
PMID: 27288083 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Snyder SH Tags: Adv Pharmacol Source Type: research

Preface.
PMID: 27288084 [PubMed - in process] (Source: Advances in Pharmacology)
Source: Advances in Pharmacology - June 13, 2016 Category: Drugs & Pharmacology Authors: Schwarcz R, Enna SJ Tags: Adv Pharmacol Source Type: research

Perspectives and Trends in Pharmacological Approaches to the Modulation of Pain.
Abstract Pharmacological approaches to our understanding and treatment of pain have had a long history and have traditionally relied on very few drugs that either have significant side effects and abuse liability, such as the nonsteroidal anti-inflammatory drugs or the opioids, respectively, or those that have been developed for other conditions such as the tricyclic antidepressants. The pathophysiology of pain is undoubtedly complex, complicated in part by the fact that it is not a singular condition, and has a variety of etiologies and a number of associated comorbidities that make treatment interventions challe...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Barrett JE, Haas DA Tags: Adv Pharmacol Source Type: research

MicroRNA-Based Biomarkers in Pain.
Abstract Biomarkers are measurable characteristics reflective of the physiological or diseased state and a crucial feature in rendering personalized medicine more precise. Dysregulated expression of circulating microRNAs (miRNAs) in bodily fluids is being explored as noninvasive clinical biomarker for a variety of disorders including chronic pain. High-precision qPCR-based signal amplification of these miRNAs enables the detection of small changes making them ideal biomarker candidates. Presence of circulating miRNAs in exosomes, small vesicles that mediate intercellular communication, opens up novel avenues for t...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Ramanathan S, Ajit SK Tags: Adv Pharmacol Source Type: research

Modulation of Chronic Pain by Metabotropic Glutamate Receptors.
Abstract Metabotropic glutamate receptors (mGluRs) belong to class C G-protein-coupled receptors. They are expressed throughout the nervous system on both neurons and glial cells. In the central nervous system (CNS), mGluRs are mainly located in the proximity of the synaptic cleft where they regulate glutamatergic transmission in addition to a number of other neurotransmitters. To date, eight subtypes of mGluRs (mGluR1-mGluR8) have been cloned and classified into three groups on the basis of sequence similarities, and pharmacological and biochemical properties. Consequently, group I mGluRs includes mGluR1 and mGlu...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Chiechio S Tags: Adv Pharmacol Source Type: research

Purinergic Mechanisms and Pain.
Abstract There is a brief introductory summary of purinergic signaling involving ATP storage, release, and ectoenzymatic breakdown, and the current classification of receptor subtypes for purines and pyrimidines. The review then describes purinergic mechanosensory transduction involved in visceral, cutaneous, and musculoskeletal nociception and on the roles played by receptor subtypes in neuropathic and inflammatory pain. Multiple purinoceptor subtypes are involved in pain pathways both as an initiator and modulator. Activation of homomeric P2X3 receptors contributes to acute nociception and activation of heterome...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Burnstock G Tags: Adv Pharmacol Source Type: research

The Role of Store-operated Calcium Channels in Pain.
Abstract Store-operated calcium channels (SOCCs) are calcium-selective cation channels. Recently, there has been explosive growth in establishing the molecular mechanisms that mediate store-operated Ca(2+) entry (SOCE) and the role of this process in normal cellular function and disease states. SOCCs and its components appear to play an important role in many Ca(2+)-dependent processes in nonexcitable cells and are implicated in several possible disorders including allergies, multiple sclerosis, cancer, and inflammatory bowel disease. Recent studies have shown that SOCCs are expressed in the central nervous system...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Munoz F, Hu H Tags: Adv Pharmacol Source Type: research

Sodium Channels in Pain and Cancer: New Therapeutic Opportunities.
Abstract Voltage-gated sodium channels (VGSCs) underpin electrical activity in the nervous system through action potential propagation. First predicted by the modeling studies of Hodgkin and Huxley, they were subsequently identified at the molecular level by groups led by Catterall and Numa. VGSC dysfunction has long been linked to neuronal and cardiac disorders with some nonselective sodium channel blockers in current use in the clinic. The lack of selectivity means that side effect issues are a major impediment to the use of broad spectrum sodium channel blockers. Nine different sodium channels are known to exis...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Luiz AP, Wood JN Tags: Adv Pharmacol Source Type: research

Antinociception by Sigma-1 Receptor Antagonists: Central and Peripheral Effects.
Abstract There is plenty of evidence supporting the modulatory role of sigma-1 receptors (σ1Rs) in nociception, mainly based on the pain-attenuated phenotype of σ1R knockout mice and on the antinociceptive effect exerted by σ1R antagonists, particularly in nonacute sensitizing conditions involving sustained afferent drive, activity-dependent plasticity/sensitization, and ultimately pain hypersensitivity, as it is the case in chronic pains of different etiology. Antinociceptive effects of σ1R antagonists both when acting alone and in combination with opioids (to enhance opioid analgesia) hav...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Romero L, Merlos M, Vela JM Tags: Adv Pharmacol Source Type: research

Central N/OFQ-NOP Receptor System in Pain Modulation.
Abstract Two decades have passed since the peptide, nociceptin/orphanin FQ (N/OFQ), and its cognate (NOP) receptor were discovered. Although NOP receptor activation causes a similar pattern of intracellular actions as mu-opioid (MOP) receptors, NOP receptor-mediated pain modulation in rodents are more complicated than MOP receptor activation. This review highlights the functional evidence of spinal, supraspinal, and systemic actions of NOP receptor agonists for regulating pain. In rodents, effects of the N/OFQ-NOP receptor system in spinal and supraspinal sites for modulating pain are bidirectional depending on th...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Kiguchi N, Ding H, Ko MC Tags: Adv Pharmacol Source Type: research

The Role of Regulatory Transporters in Neuropathic Pain.
Abstract Neuropathic pain arises from an injury or disease of the somatosensory nervous system rather than stimulation of pain receptors. As a result, the fine balance between excitation and inhibition is perturbed leading to hyperalgesia and allodynia. Various neuropathic pain models provide considerable evidence that changes in the glutamatergic, GABAergic, and monoaminergic systems. Neurotransmitter reuptake transporter proteins have the potential to change the temporal and spatial profile of various neurotransmitters throughout the nervous system. This, in turn, can affect the downstream effects of these neuro...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Yousuf MS, Kerr BJ Tags: Adv Pharmacol Source Type: research

The Pharmacology of Visceral Pain.
Abstract Visceral pain describes pain emanating from the internal thoracic, pelvic, or abdominal organs. Unlike somatic pain, visceral pain is generally vague, poorly localized, and characterized by hypersensitivity to a stimulus such as organ distension. While current therapeutics provides some relief from somatic pain, drugs used for treatment of chronic visceral pain are typically less efficacious and limited by multiple adverse side effects. Thus, the treatment of visceral pain represents a major unmet medical need. Further, more basic research into the physiology and pathophysiology of visceral pain is needed...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Johnson AC, Greenwood-Van Meerveld B Tags: Adv Pharmacol Source Type: research

Preclinical Pharmacological Approaches in Drug Discovery for Chronic Pain.
Abstract In recent years, animal behavioral models, particularly those used in pain research, have been increasingly scrutinized and criticized for their role in the poor translation of novel pharmacotherapies for chronic pain. This chapter addresses the use of animal models of pain used in drug discovery research. It highlights how, when, and why animal models of pain are used as one of the many experimental tools used to gain better understanding of target mechanisms and rank-order compounds in the iterative process of establishing structure-activity relationship. Together, these models help create an "anal...
Source: Advances in Pharmacology - February 29, 2016 Category: Drugs & Pharmacology Authors: Whiteside GT, Pomonis JD, Kennedy JD Tags: Adv Pharmacol Source Type: research