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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

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