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

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