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Author: John Fleites
Publisher:
ISBN:
Category :
Languages : en
Pages : 41
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Book Description
Pain signaling is sensed by dorsal root ganglion (DRG) neurons. After nerve injury, DRG neurons can become hyperexcitable and generate a chronic and painful phenotype known as neuropathic pain. The exact underlying cellular mechanisms precipitating neuropathic pain are unclear, but altered ion channel properties are key in determining DRG neuronal hyperexcitability. One class of ion channels known as the sodium activated potassium (KNa) channels have been shown to regulate the resting membrane potential (RMP) and control firing accommodation in these neurons, and could very well be a central player in neuropathic pain. Multiple lines of evidence have indicated that p38 Mitogen Activated Protein Kinase (p38 MAPK) activity is important during neuropathic pain. Indeed, it has been recently shown that p38 MAPK facilitates neuronal regeneration after nerve crush of the sciatic nerve. Because of the roles of p38 MAPK in neuropathy and KNa channel involvement in DRG neuronal excitability, I sought to determine whether p38 MAPK regulates KNa channels in DRG neurons. I used anisomycin, a p38 MAPK activator, and a p38 MAPK Inhibitor to study the effects of p38 MAPK on potassium currents in rat embryonic DRG neurons and Slack KNa channels in heterologous expression systems. I show that KNa currents are upregulated by p38 MAPK in DRG neurons; Slack currents are also modulated by p38 MAPK. Using site-directed mutagenesis, I have shown that mutating one of Slack's putative p38 phosphorylation sites to glutamic acid significantly speeds up activation kinetics. These results suggest that KNa channels regulated by p38 MAPK in DRG neurons act to prevent hyperexcitability and may aid in the neuronal regeneration process after nerve injury.
Author: John Fleites
Publisher:
ISBN:
Category :
Languages : en
Pages : 41
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Book Description
Pain signaling is sensed by dorsal root ganglion (DRG) neurons. After nerve injury, DRG neurons can become hyperexcitable and generate a chronic and painful phenotype known as neuropathic pain. The exact underlying cellular mechanisms precipitating neuropathic pain are unclear, but altered ion channel properties are key in determining DRG neuronal hyperexcitability. One class of ion channels known as the sodium activated potassium (KNa) channels have been shown to regulate the resting membrane potential (RMP) and control firing accommodation in these neurons, and could very well be a central player in neuropathic pain. Multiple lines of evidence have indicated that p38 Mitogen Activated Protein Kinase (p38 MAPK) activity is important during neuropathic pain. Indeed, it has been recently shown that p38 MAPK facilitates neuronal regeneration after nerve crush of the sciatic nerve. Because of the roles of p38 MAPK in neuropathy and KNa channel involvement in DRG neuronal excitability, I sought to determine whether p38 MAPK regulates KNa channels in DRG neurons. I used anisomycin, a p38 MAPK activator, and a p38 MAPK Inhibitor to study the effects of p38 MAPK on potassium currents in rat embryonic DRG neurons and Slack KNa channels in heterologous expression systems. I show that KNa currents are upregulated by p38 MAPK in DRG neurons; Slack currents are also modulated by p38 MAPK. Using site-directed mutagenesis, I have shown that mutating one of Slack's putative p38 phosphorylation sites to glutamic acid significantly speeds up activation kinetics. These results suggest that KNa channels regulated by p38 MAPK in DRG neurons act to prevent hyperexcitability and may aid in the neuronal regeneration process after nerve injury.
Author: Megan Nuwer
Publisher:
ISBN:
Category :
Languages : en
Pages : 81
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Book Description
Inflammatory pain occurs as a result of tissue injury. During inflammation, a complex neuron-immune interaction arises, characterized by nociceptive sensitization and hyperalgesia. Nociceptor sensitization is the direct result of hyperexcitability of the pain-sensing neurons located within the dorsal root ganglion (DRG). DRG neuronal hyperexcitability is caused by activation of second messsenger pathways by immune factors, which alter ion channel conductances in the neuron. Previous studies have shown that the protein kinase A (PKA) pathway is critical for DRG hyperexcitability and inflammatory pain. However, the mechanisms by which PKA activation leads to hyperexcitability largely remain unresolved. Here, I examined the effect of PKA on the Na+-activated K+ conductance, (KNa), that is highly expressed in DRG neurons. The goal of my work was to determine if and how PKA modulates KNa.^Specifically, I looked at (1) if PKA affects the KNa channel subunit Slack expressed heterologously in HEK-293 and CHO cells and (2) if PKA affects KNa in DRG neurons. My results showed that although recombinant Slack channels are unaffected by PKA, PKA activation does cause a decrease in KNa in DRG neurons. I then showed that the decrease is due to the internal trafficking of Slack channels from the DRG membrane, and not due to an inhibition in channel gating. (1) The C-terminal of the KNa channel subunit, Slack contains several putative PKA phosphorylation consensus sites. While previous studies have shown modulation of recombinant Slack channels by protein kinase C, the effect of PKA phosphorylation on these channels has not been examined. In this study, I investigated if Slack serves as a substrate for phosphorylation by PKA and what effect this phosphorylation has on Slack channel gating in heterologous expression systems. I found that the Slack protein is phosphorylated by PKA.^Using electrophysiological techniques to examine Slack channel activity however, I found that in HEK and CHO cells, there is no effect of PKA activation on Slack channel activity. These results suggested that additional factors, not present in heterologous expression systems, may be needed for PKA to exert its effect on Slack. (2) PKA is known to play an important role in nociceptive sensitization characterized by DRG hyperexcitability. Although Slack is highly expressed in DRG neurons, its role in sensitization and hyperexcitability has not been previously described. In this study, I investigated the effect of PKA activation on KNa in DRG neurons. In DRG neurons, I found that PKA activation led to a loss of firing accommodation of the neurons, resulting in hyperexcitability. I also found that KNa is significantly decreased in response to PKA.^While KNa channel activity is unaffected by PKA, I found there was a significant reduction in the membrane expression levels of the KNa channel subunit Slack after PKA activation. The decrease in Slack membrane expression may be responsible for the loss of firing accommodation observed in these neurons after PKA activation. These results suggest that KNa may be involved in nociceptive sensitization and could be a novel target for the development of new analgesics.
Author: Ellen Kinson Wittmack
Publisher:
ISBN:
Category :
Languages : en
Pages : 284
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Book Description
Author: Lei Zhou
Publisher: Springer Nature
ISBN: 9811642540
Category : Medical
Languages : en
Pages : 407
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Book Description
This book gathers relatively recent and significant topics in the field of ion channel research. Ion channels form the molecular basis for membrane excitability in cells present in the cardiovascular and nervous systems. In many non-excitable cells, ion channels contribute to diverse physiological functions, including the secretion of signaling compounds like hormones and insulin, cell volume regulation, intracellular signaling, especially Ca2+ signaling, etc. Many human diseases have been attributed to abnormal channel functions and defective membrane expression of channel proteins. On the other hand, ion channels are excellent models for studying protein biophysics, especially the allosteric regulation of protein function by miscellaneous stimuli. Therefore, research on ion channels carries significant meaning for the understanding of basic protein biophysics and diverse physiological functions. Such vital information also assists in developing novel and effective treatments for related human diseases. This book provides graduates and scientists in both basic and clinical levels a comprehensive understanding of cutting-edge advances and a useful and stimulating platform for tackling their own questions about ion channels.
Author:
Publisher: Academic Press
ISBN: 0080857779
Category : Science
Languages : en
Pages : 317
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Book Description
Neuromuscular Junctions in Drosophila gathers the main contributions that research using the fruit fly Drosophila melanogaster has made in the area of synapse development, synapse physiology, and excitability of muscles and nerve cells. The chapters in this book represent a synthesis of major advances in our understanding of neuronal development and synaptic physiology, which have been obtained using the above approach.This book is directed to the general neuroscience audience: researchers, instructors, graduate students, and advanced undergraduates who are interested in the mechanisms of synapse development and physiology. However, the book will also be a valuable resource for those that use the fruit fly as a model system in their laboratories.Key Features* Synthesizes the genetic approaches used to study synaptic development and function at the neuromuscular junction, using flies as a model system* Covers major recent advances in muscle development, pathfinding, synapse maturation and plasticity, exo- and endocytosis, and ion channel function* Written in clear language that is easily understandable to readers not already familiar with fruit fly research* Includes numerous diagrams and extensive reference lists
Author: Irwin B. Levitan
Publisher: Oxford University Press, USA
ISBN: 9780195145236
Category : Molecular neurobiology
Languages : en
Pages : 640
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Book Description
Intended for use by advanced undergraduate, graduate and medical students, this book presents a study of the unique biochemical and physiological properties of neurons, emphasising the molecular mechanisms that generate and regulate their activity.
Author: John N. Wood
Publisher: Oxford University Press, USA
ISBN: 0190860502
Category : Medical
Languages : en
Pages : 939
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Book Description
This handbook is currently in development, with individual articles publishing online in advance of print publication. At this time, we cannot add information about unpublished articles in this handbook, however the table of contents will continue to grow as additional articles pass through the review process and are added to the site. Please note that the online publication date for this handbook is the date that the first article in the title was published online.
Author: Sanjeev Kumar Singh
Publisher: Springer Nature
ISBN: 9811589364
Category : Science
Languages : en
Pages : 334
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Book Description
This book presents various computer-aided drug discovery methods for the design and development of ligand and structure-based drug molecules. A wide variety of computational approaches are now being used in various stages of drug discovery and development, as well as in clinical studies. Yet, despite the rapid advances in computer software and hardware, combined with the exponential growth in the available biological information, there are many challenges that still need to be addressed, as this book shows. In turn, it shares valuable insights into receptor-ligand interactions in connection with various biological functions and human diseases. The book discusses a wide range of phylogenetic methods and highlights the applications of Molecular Dynamics Simulation in the drug discovery process. It also explores the application of quantum mechanics in order to provide better accuracy when calculating protein-ligand binding interactions and predicting binding affinities. In closing, the book provides illustrative descriptions of major challenges associated with computer-aided drug discovery for the development of therapeutic drugs. Given its scope, it offers a valuable asset for life sciences researchers, medicinal chemists and bioinformaticians looking for the latest information on computer-aided methodologies for drug development, together with their applications in drug discovery.
Author: Denis Alexander
Publisher: Handbook of Experimental Pharmacology
ISBN:
Category : Medical
Languages : en
Pages : 476
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Book Description
with contributions by numerous experts
Author: Nicholas Sperelakis
Publisher: Elsevier
ISBN: 0080574556
Category : Science
Languages : en
Pages : 1262
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Book Description
This authoritative book gathers together a broad range of ideas and topics that define the field. It provides clear, concise, and comprehensive coverage of all aspects of cellular physiology from fundamental concepts to more advanced topics. The Third Edition contains substantial new material. Most chapters have been thoroughly reworked. The book includes chapters on important topics such as sensory transduction, the physiology of protozoa and bacteria, the regulation of cell division, and programmed cell death. - Completely revised and updated - includes 8 new chapters on such topics as membrane structure, intracellular chloride regulation, transport, sensory receptors, pressure, and olfactory/taste receptors - Includes broad coverage of both animal and plant cells - Appendixes review basics of the propagation of action potentials, electricity, and cable properties - Authored by leading experts in the field - Clear, concise, comprehensive coverage of all aspects of cellular physiology from fundamental concepts to more advanced topics
