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Toxins in Drug Discovery and Pharmacology

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ISBN: 9783038428619 9783038428626 Year: Pages: XII, 304 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Public Health
Added to DOAB on : 2018-05-04 11:37:49
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Venoms from marine and terrestrial animals (cone snails, scorpions, spiders, snakes, centipedes, cnidarian, etc.) can be seen as untapped cocktails of biologically active compounds that are being increasingly recognized as a new emerging source of peptide-based therapeutics. Venomous animals are considered to be specialized predators that have evolved the most sophisticated peptide chemistry and neuropharmacology for their own biological purposes by producing venoms that contain a structural and functional diversity of neurotoxins. These neurotoxins appear to be highly selective ligands for a wide range of ion channels and receptors. Therefore, they represent interesting lead compounds for the development of analgesics, anti-cancer drugs, drugs for neurological disorders such as multiple sclerosis, Parkinson' s disease, Alzheimer' s disease, and other therapeutics.This Special Issue of Toxins aims to provide a comprehensive look at toxins and toxin-inspired leads and will focus on the mechanisms of action, structure–function relationships, and evolution of pharmacologically interesting venom components, including the most recent developments related to the emergence of venoms as an underutilized source of highly evolved bioactive peptides with clinical potential.

Ion Channel Trafficking and Cardiac Arrhythmias

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889456437 Year: Pages: 123 DOI: 10.3389/978-2-88945-643-7 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Physiology
Added to DOAB on : 2019-01-23 14:53:43
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A well-adjusted expression of cardiac ion channels at the sarcolemma is of crucial importance for normal action potential formation and thus cardiac function. The cellular processes that transport channel proteins from the endoplasmic reticulum towards specified regions on the sarcolemmal membrane, and subsequently take them from the plasma membrane to the protein degradation machinery are commonly known as trafficking. The research field recognizes that aberrant channel trafficking stands at the basis of many congenital and acquired arrhythmias. The collection of papers in this eBook provides state-of-the-art insight into the world of ion channel trafficking research.

ATP-gated P2X receptors in Health and Disease

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194056 Year: Pages: 172 DOI: 10.3389/978-2-88919-405-6 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2015-12-10 11:59:06
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Extracellular ATP is currently recognized as one of the most widely distributed neurotransmitters and neuromodulators in the peripheral and central nervous system. ATP-gated P2X receptors are expressed by neurons, glial and many other non-neuronal cells and represent an attractive target for therapeutic interventions. Diverse molecular and cellular mechanisms have been identified for P2X receptor functioning, including the ability to enlarge the size of the ion pore associated with the release of several key immune molecules. A major recent breakthrough was the determination of the X-ray crystal structures of zebrafish P2X4 receptor in ATP-bound and ATP-free states. The P2X receptor research field is rapidly growing, as evidenced by the almost 2000 papers published in the last 5 years. However, despite the fundamental signalling function of extracellular ATP in the nervous system, the widespread roles of P2X receptors have not been widely elucidated and presented in textbooks. In this volume of papers we aim to gather a collection of high quality papers, detailing the latest insights from the most accomplished international P2X receptor researchers. Importantly, basic research into P2X receptors has a strong translational impact and our collection of articles could be a valuable guide for the development of new pharmacological and biotechnological tools addressing the function of P2X receptors. Within this collection we plan to cover receptor structure-function relationships, receptors trafficking, to highlight the special properties of P2X receptors and their pharmacological profiles, and to describe the translational aspects of cellular ATP signaling in pain and in other neurological and vascular diseases.

CaMKII in Cardiac Health and Disease

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192991 Year: Pages: 165 DOI: 10.3389/978-2-88919-299-1 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Medicine (General) --- Therapeutics --- Science (General)
Added to DOAB on : 2015-12-10 11:59:07
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The calcium-calmodulin dependent protein kinases (CaMKs) are a broadly expressed family of calcium-sensitive intracellular kinases, which are responsible for transducing cytosolic calcium signals into phosphorylation-based regulation of proteins and physiological functions. As the multifunctional member of the family, CaMKII has become the most prominent for its roles in the central nervous system and heart, where it controls a diverse range of calcium-dependent processes; from learning and memory at the neuronal synapse, to cellular growth and death in the myocardium. In the heart, CaMKII directly regulates many of the most important ion channels and calcium handling proteins, and controls the expression of an ever-increasing number of transcripts and their downstream products. Functionally, these actions are thought to orchestrate many of the electrophysiologic and contractile adaptations to common cardiac stressors, such as rapid pacing, chronic adrenergic stimulation, and oxidative challenge. In the context of disease, CaMKII has been shown to contribute to a remarkably wide variety of cardiac pathologies, of which heart failure (HF) is the most conspicuous. Hyperactivity of CaMKII is an established contributor to pathological cardiac remodeling, and is widely thought to directly promote arrhythmia and contractile dysfunction during HF. Moreover, several non-failing arrhythmia-susceptible phenotypes, which result from specific genetic channelopathies, functionally mimic constitutive channel phosphorylation by CaMKII. Because CaMKII contributes to both the acute and chronic manifestations of major cardiac diseases, but may be only minimally required for homeostasis in the absence of chronic stress, it has come to be one of the most promising therapeutic drug targets in cardiac biology. Thus, development of more specific and deliverable small molecule antagonists remains a key priority for the field. Here we provide a selection of articles to summarize the state of our knowledge regarding CaMKII in cardiac health and disease, with a particular view to highlighting recent developments in CaMKII activation, and new targets in CaMKII-mediated control of myocyte physiology.

The truth in complexes: why unraveling ion channel multi-protein signaling nexuses is critical for understanding the function of the nervous system

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194452 Year: Pages: 160 DOI: 10.3389/978-2-88919-445-2 Language: English
Publisher: Frontiers Media SA
Subject: Neurology --- Science (General)
Added to DOAB on : 2016-02-05 17:24:33
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In the search for simple explanations of the natural world, its complicated textures are often filed down to a smoothened surface of our liking. The impetus for this Research Topic was borne out of a need to re-ignite interest in the complex – in this case in the context of ion channels in the nervous system. Ion channels are the large proteins that form regulated pores in the membranes of cells and, in the brain, are essential for the transfer, processing and storage of information. These pores full of twists and turns themselves are not just barren bridges into cells. More and more we are beginning to understand that ion channels are like bustling medieval bridges (packed with apartments and shops) rather than the more sleek modern variety – they are dynamic hubs connected with many structures facilitating associated activities. Our understanding of these networks continues to expand as our investigative tools advance. Together these articles highlight how the complexity of ion channel signaling nexuses is critical to the proper functioning of the nervous system.

Hemichannels; from the molecule to the function

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194674 Year: Pages: 122 DOI: 10.3389/978-2-88919-467-4 Language: English
Publisher: Frontiers Media SA
Subject: Physiology --- Science (General)
Added to DOAB on : 2016-03-10 08:14:32
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Coordinated cell interactions are required to accomplish several complex and dynamic tasks observed in several tissues. Cell function may be coordinated by cell-to-cell communication through gap junctions channels (GJCs). These channels are formed by the serial docking of two hemichannels, which in turn are formed by six protein subunits called connexins (Cxs). It is well known that GJCs are involved in several functions, such as intercellular propagation of calcium waves, spread of electrotonic potentialsand spatial buffering of ions and metabolites. On the other hand, undocked hemichannels, which are not forming GJCs, can also serve other functions as “free hemichannels”. Currently, it is recognized that undocked hemichannels may have functional relevance in cell physiology allowing diffusional exchange of ions and small molecules between intra- and extra-cellular compartments. Additionally, another family of proteins calls pannexins (Panx) also forms functional hemichannels at the plasma membrane. Recently, Panxhemichannels have been involved in both pathological and physiological processes. Controlled hemichannel opening allows the release of small signaling molecules including ATP, glutamate, NAD+, adenosine, cyclic nucleotides, PGE2. They also allow uptake of relevant signaling molecules (e.g., cADPR) and metabolites (e.g., glucose). Additionally, a growing body of evidence shows that hemichannels are involved in important processes, such glucose detection in tanicytes, activation of the inflammasome, memory consolidation in the basolateral amygdala, potentiation of muscle contraction and release of nitric oxide from endothelial cells, among others. However, hemichannels can also play an important role in the homeostatic imbalance observed in diverse chronic diseases. In fact, massive and/or uncontrolled hemichannel opening induces or accelerates cell death in several pathological conditions including Charcot-Marie-Tooth disease, ischemia, oculodentodigital dysplasia, hydrotic ectodermic dysplasia, inflammatory responses, and deafness. Hemichannel-mediated cell death is due mainly to an entry of Ca+2. The latter activates proteases, nucleases and lipases, causing irreversible cell damage. An increasing amount of evidence demonstrates that blockade of uncontrolled hemichannel opening greatly reduces the cellular damage observed in several chronic diseases models. Therefore, Cx and Panx-hemichannels appear as promising drug targets for clinical treatment of human chronic diseases. Therefore, pharmacological tools are urgently needed to further elucidate hemichannels functions and to validate them as drug targets for the development of novel therapies for connexin-based diseases. Thus, understanding the role of Cx and Panx-hemichannels under physiological conditions and recognizing the molecular mechanisms controlling them, may provide us with a better picture of the hemichannels participation in some diseases and of the signals underlying their malfunctioning.

Interplay of Connexins and Pannexins in Tissue Function and Disease

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ISBN: 9783038973928 9783038973935 Year: Pages: 380 DOI: 10.3390/books978-3-03897-393-5 Language: English
Publisher: MDPI - Multidisciplinary Digital Publishing Institute
Subject: Biology
Added to DOAB on : 2018-11-30 12:13:56
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This Special Issue is related to the 18th biannual International Gap Junction Conference (IGJC2017), which has been held at the Crowne Plaza Hotel, Glasgow and hosted by Glasgow Caledonian University, 29 July–3 August, 2017. This Special Issue, entitled “Interplay of Connexins and Pannexins in Tissue Function and Disease”, focuses on six key state-of-the-art reviews, written by leads in the field on cutting edge topics and the latest developments in clinical trials in diverse organ systems. A further 14 original articles contributed by delegates attending the meeting are also included and celebrate 50 years of Gap Junction Research.Topics: Connexins and Pannexins:•Trafficking, Assembly, Gating, and Protein–Protein Interactions•Roles in the Cardiovascular System•Roles in Tumorigenesis•Roles in Epithelial Tissue and Wound Healing •Connexin Therapy Translated to Clinic

Involvements of TRP Channels and Oxidative Stress in Pain

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889455959 Year: Pages: 126 DOI: 10.3389/978-2-88945-595-9 Language: English
Publisher: Frontiers Media SA
Subject: Science (General) --- Physiology
Added to DOAB on : 2019-01-23 14:53:43
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Undoubtedly, pain conditions the quality of life of millions of people worldwide suffering a wide range of diseases. Major research efforts are being made by the international scientific community to determine the mechanisms underlying nociception. Growing evidence points out a complex network including oxidative and nitrosative stress, inflammatory response and cation signaling. In this sense, transient receptor potential (TRP) channels have attracted researchers’ attention. Expression levels are very different in tissues and cells mediating a myriad of processes in our organism. At the neurological level, it has been observed that the expression levelsof four TRP channels (TRPA1, TRPM2, TRPV1, and TRPV4) are high in neurons related to nociception, including dorsal root ganglion and trigeminal ganglia neurons. For this reason, this research field promises to shed light on this intricated matrix linking oxidative stress, calcium signaling (via TRP channels), and inflammatory signals in different pain modalities, including neuropathic pain and chemotherapy-induced peripheral pain. In such a way, all this intense research activity will enable us to design individual and rational treatment strategies for pain relief, such as the use of molecular neurosurgery.

Mitochondria: the cell powerhouse and nexus of stress

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192830 Year: Pages: 121 DOI: 10.3389/978-2-88919-283-0 Language: English
Publisher: Frontiers Media SA
Subject: Biology --- Physiology --- Science (General)
Added to DOAB on : 2015-12-10 11:59:06
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Mitochondrion, a sub-cellular organelle originated from primary endosymbiosis, plays a vital role in energy metabolism of eukaryotic cells. The transfer of electrons through the electron transport chain (ETC) to molecular oxygen accompanied by the extrusion of protons from the matrix generate an electrochemical gradient across the inner mitochondrial membrane (IMM) that is used for ATP synthesis by oxidative phosphorylation. Despite many aspects of ATP synthesis have been delineated, regulatory mechanisms responsible for energy synthesis and transfer still remain to be uncovered. In addition to energy function, mitochondria play a crucial role in cell metabolism under both physiological and pathological conditions through their participation in many intracellular signaling pathways. Studies over the last 30 years provide strong evidence that mitochondria are the nexus of various stresses which initiate cell death through apoptosis, oncosis, necrosis and autophagy depending on the severity of the stress and cellular energy status. The release of several pro-apoptotic proteins such as cytochrome c, Smac/DIABLO, AIF, endonuclease G from intermembrane space initiates both caspase-dependent and caspase-independent apoptosis. The formation of the mitochondrial permeability transition pore in the IMM promotes cell death mostly through necrosis whereas a mild stress activates autophagy. Due to their critical roles in both cell death and survival mitochondria have been widely considered as an important target for various pharmacological and conditional therapeutic approaches. Currently, a large number of mitochondria-targeted agents are suggested to prevent (in ischemia reperfusion injury, cardiovascular, neurodegenerative and other diseases) or stimulate (in various cancers) cell death. This Research Topic focuses on the role of mitochondria in the regulation of cell metabolism and signaling under physiological and pathological conditions. Studies performed on cultured cells and isolated organs/tissues using different animal and cellular models of various diseases are also included and discussed.

Ca2+ Signaling and Heart Rhythm

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889198740 Year: Pages: 133 DOI: 10.3389/978-2-88919-874-0 Language: English
Publisher: Frontiers Media SA
Subject: Physiology --- Science (General)
Added to DOAB on : 2016-01-19 14:05:46
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Ca2+ is a key second messenger in the intricate workings of the heart. In cardiac myocytes, Ca2+ signaling controls or modulates electrophysiological function, excitation-contraction coupling, contractile function, energy balance, cell death, and gene transcription. Thus, diverse Ca2+-dependent regulatory processes occur simultaneously within a cell. Yet, distinct signals can be resolved by local Ca2+ sensitive protein complexes and differential Ca2+ signal integration. In addition to its importance to normal cardiac function, such regulation is also crucial in disease conditions. Ca2+ is likely involved in ectopic cardiac rhythms in both atrial and ventricular tissues through generating triggered activity often appearing as delayed afterdepolarisations, particularly following cellular Ca overloading. Recent studies also implicate Ca2+ in Na+ channel expression and properties with consequences for conduction velocity and therefore arrhythmic substrate. At the cellular level, such regulation involves control of the activity of membrane ion channels and Ca2+ handling proteins. These in turn involve multiple extra- and intracellular signaling pathways. This e-book assembles review and original articles from experts in this field. It summarises major recent progress bearing on roles of Ca2+ in cardiac electrophysiological function encompassing both normal and abnormal cardiac function. These extend from physiological roles of Ca2+ signaling in pacemaker function, in particular generation of sino-atrial pacemaker potentials, to pathological roles of abnormal Ca2+ signaling in both atrial and ventricular arrhythmogenesis. It also seeks to bridge the gap between advances in basic science and development of new therapies.

Keywords

Ca2+ --- Heart --- Pak1 --- SA node --- voltage gated Ca2+ channels --- TRPC --- STIM1 --- Orai1 --- PP2A

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