Ion Channels: Structural Basis for Function and Disease
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Paramyotonia Congenita
Paramyotonia congenita Description Paramyotonia congenita is a disorder that affects muscles used for movement (skeletal muscles). Beginning in infancy or early childhood, people with this condition experience bouts of sustained muscle tensing (myotonia) that prevent muscles from relaxing normally. Myotonia causes muscle stiffness that typically appears after exercise and can be induced by muscle cooling. This stiffness chiefly affects muscles in the face, neck, arms, and hands, although it can also affect muscles used for breathing and muscles in the lower body. Unlike many other forms of myotonia, the muscle stiffness associated with paramyotonia congenita tends to worsen with repeated movements. Most people—even those without muscle disease—feel that their muscles do not work as well when they are cold. This effect is dramatic in people with paramyotonia congenita. Exposure to cold initially causes muscle stiffness in these individuals, and prolonged cold exposure leads to temporary episodes of mild to severe muscle weakness that may last for several hours at a time. Some older people with paramyotonia congenita develop permanent muscle weakness that can be disabling. Frequency Paramyotonia congenita is an uncommon disorder; it is estimated to affect fewer than 1 in 100,000 people. Causes Mutations in the SCN4A gene cause paramyotonia congenita. This gene provides instructions for making a protein that is critical for the normal function of skeletal muscle cells. For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of positively charged atoms (ions), including sodium, into skeletal muscle cells. The SCN4A protein forms channels that control the flow of sodium ions into these cells. -
Neuromyotonia in Hereditary Motor Neuropathy J Neurol Neurosurg Psychiatry: First Published As 10.1136/Jnnp.54.3.230 on 1 March 1991
230 Journal ofNeurology, Neurosurgery, and Psychiatry 1991;54:230-235 Neuromyotonia in hereditary motor neuropathy J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.54.3.230 on 1 March 1991. Downloaded from A F Hahn, A W Parkes, C F Bolton, S A Stewart Abstract Case II2 Two siblings with a distal motor This 15 year old boy had always been clumsy. neuropathy experienced cramping and Since the age of 10, he had noticed generalised difficulty in relaxing their muscles after muscle stiffness which increased with physical voluntary contraction. Electromyogra- activity such as walking upstairs, running and phic recordings at rest revealed skating. For some time, he was aware of repetitive high voltage spontaneous elec- difficulty in releasing his grip and his fingers trical discharges that were accentuated tended to cramp on writing. He had noticed after voluntary contraction and during involuntary twitching of his fingers, forearm ischaemia. Regional neuromuscular muscles and thighs at rest and it was more blockage with curare indicated hyperex- pronounced after a forceful voluntary con- citability of peripheral nerve fibres and traction. Muscle cramping and spontaneous nerve block suggested that the ectopic muscle activity were particularly unpleasant activity originated in proximal segments when he re-entered the house in the winter, of the nerve. Symptoms were improved for example, after a game of hockey. Since the with diphenylhydantoin, carbamazepine age of twelve, he had noticed a tendency to and tocainide. trip. Subsequently he developed bilateral foot drop and weakness of his hands. He denied sensory symptoms and perspired only with The term "neuromyotonia" was coined by exertion. -
Slow Inactivation in Voltage Gated Potassium Channels Is Insensitive to the Binding of Pore Occluding Peptide Toxins
Biophysical Journal Volume 89 August 2005 1009–1019 1009 Slow Inactivation in Voltage Gated Potassium Channels Is Insensitive to the Binding of Pore Occluding Peptide Toxins Carolina Oliva, Vivian Gonza´lez, and David Naranjo Centro de Neurociencias de Valparaı´so, Facultad de Ciencias, Universidad de Valparaı´so, Valparaı´so, Chile ABSTRACT Voltage gated potassium channels open and inactivate in response to changes of the voltage across the membrane. After removal of the fast N-type inactivation, voltage gated Shaker K-channels (Shaker-IR) are still able to inactivate through a poorly understood closure of the ion conduction pore. This, usually slower, inactivation shares with binding of pore occluding peptide toxin two important features: i), both are sensitive to the occupancy of the pore by permeant ions or tetraethylammonium, and ii), both are critically affected by point mutations in the external vestibule. Thus, mutual interference between these two processes is expected. To explore the extent of the conformational change involved in Shaker slow inactivation, we estimated the energetic impact of such interference. We used kÿconotoxin-PVIIA (kÿPVIIA) and charybdotoxin (CTX) peptides that occlude the pore of Shaker K-channels with a simple 1:1 stoichiometry and with kinetics 100-fold faster than that of slow inactivation. Because inactivation appears functionally different between outside-out patches and whole oocytes, we also compared the toxin effect on inactivation with these two techniques. Surprisingly, the rate of macroscopic inactivation and the rate of recovery, regardless of the technique used, were toxin insensitive. We also found that the fraction of inactivated channels at equilibrium remained unchanged at saturating kÿPVIIA. -
Glycine311, a Determinant of Paxilline Block in BK Channels: a Novel Bend in the BK S6 Helix Yu Zhou Washington University School of Medicine in St
Washington University School of Medicine Digital Commons@Becker Open Access Publications 2010 Glycine311, a determinant of paxilline block in BK channels: A novel bend in the BK S6 helix Yu Zhou Washington University School of Medicine in St. Louis Qiong-Yao Tang Washington University School of Medicine in St. Louis Xiao-Ming Xia Washington University School of Medicine in St. Louis Christopher J. Lingle Washington University School of Medicine in St. Louis Follow this and additional works at: http://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Zhou, Yu; Tang, Qiong-Yao; Xia, Xiao-Ming; and Lingle, Christopher J., ,"Glycine311, a determinant of paxilline block in BK channels: A novel bend in the BK S6 helix." Journal of General Physiology.135,5. 481-494. (2010). http://digitalcommons.wustl.edu/open_access_pubs/2878 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Published April 26, 2010 A r t i c l e Glycine311, a determinant of paxilline block in BK channels: a novel bend in the BK S6 helix Yu Zhou, Qiong-Yao Tang, Xiao-Ming Xia, and Christopher J. Lingle Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110 The tremorogenic fungal metabolite, paxilline, is widely used as a potent and relatively specific blocker of Ca2+- and voltage-activated Slo1 (or BK) K+ channels. The pH-regulated Slo3 K+ channel, a Slo1 homologue, is resistant to blockade by paxilline. -
What Is a Skeletal Muscle Channelopathy?
Muscle Channel Patient Day 2019 Dr Emma Matthews The Team • Professor Michael Hanna • Emma Matthews • Doreen Fialho - neurophysiology • Natalie James – clinical nurse specialist • Sarah Holmes - physiotherapy • Richa Sud - genetics • Roope Mannikko – electrophysiology • Iwona Skorupinska – research nurse • Louise Germain – research nurse • Kira Baden- service manager • Jackie Kasoze-Batende– NCG manager • Jean Elliott – NCG senior secretary • Karen Suetterlin, Vino Vivekanandam • – research fellows What is a skeletal muscle channelopathy? Muscle and nerves communicate by electrical signals Electrical signals are made by the movement of positively and negatively charged ions in and out of cells The ions can only move through dedicated ion channels If the channel doesn’t work properly, you have a “channelopathy” Ion channels CHLORIDE CHANNELS • Myotonia congenita – CLCN1 • Paramyotonia congenita – SCN4A MYOTONIA SODIUM CHANNELS • Hyperkalaemic periodic paralysis – SCN4A • Hypokalaemic periodic paralysis – 80% CACNA1S CALCIUM CHANNELS – 10% SCN4A PARALYSIS • Andersen-Tawil Syndrome – KCNJ2 POTASSIUM CHANNELS Myotonia and Paralysis • Two main symptoms • Paralysis = an inexcitable muscle – Muscles are very weak or paralysed • Myotonia = an overexcited muscle – Muscle keeps contracting and become “stuck” - Nerve action potential Cl_ - + - + + + Motor nerve K+ + Na+ Na+ Muscle membrane Ach Motor end plate T-tubule Nav1.4 Ach receptors Cav1.1 and RYR1 Muscle action potential Calcium MuscleRelaxed contraction muscle Myotonia Congenita • Myotonia -
Gain-Of-Function Mutation in Nav 1.7 in Familial Erythromelalgia Induces Bursting of Sensory Neurons
Gain-of-function mutation in Nav 1.7 in familial erythromelalgia induces bursting of sensory neurons S. D. Dib-Hajj,1,2,3 A. M. Rush,1,2,3 T. R. Cummins,4 F. M. Hisama,1 S. Novella,1 L. Tyrrell,1,2,3, L. Marshall1 and S. G. Waxman1,2,3 1Department of Neurology and 2Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, 3Rehabilitation Research Center, VA Connecticut Healthcare System, West Haven, CT and 4Department of Pharmacology and Toxicology, Stark Neurosciences Institute, Indiana University School of Medicine, Indianapolis, IN, USA Correspondence to: Stephen G. Waxman, MD, PhD, Department of Neurology, LCI 707, Yale School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA E-mail: [email protected] Erythromelalgia is an autosomal dominant disorder characterized by burning pain in response to warm stimuli or moderate exercise. We describe a novel mutation in a family with erythromelalgia in SCN9A, the gene that encodes the Nav1.7 sodium channel. Nav1.7 produces threshold currents and is selectively expressed within sensory neurons including nociceptors. We demonstrate that this mutation, which produces a hyperpolarizing shift in activation and a depolarizing shift in steady-state inactivation, lowers thresholds for single action potentials and high frequency firing in dorsal root ganglion neurons. Erythromelalgia is the first inherited pain disorder in which it is possible to link a mutation with an abnormality in ion channel function and with altered firing of pain signalling neurons. Keywords: channel; channelopathy; erythromelalgia; mutation; pain; sodium Abbreviations: DRG = dorsal root ganglion Received January 25, 2005. -
Severe Infantile Hyperkalaemic Periodic Paralysis And
1339 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.74.9.1339 on 21 August 2003. Downloaded from SHORT REPORT Severe infantile hyperkalaemic periodic paralysis and paramyotonia congenita: broadening the clinical spectrum associated with the T704M mutation in SCN4A F Brancati, E M Valente, N P Davies, A Sarkozy, M G Sweeney, M LoMonaco, A Pizzuti, M G Hanna, B Dallapiccola ............................................................................................................................. J Neurol Neurosurg Psychiatry 2003;74:1339–1341 the face and hand muscles, and paradoxical myotonia. Onset The authors describe an Italian kindred with nine individu- of paramyotonia is usually at birth.2 als affected by hyperkalaemic periodic paralysis associ- HyperPP/PMC shows characteristics of both hyperPP and ated with paramyotonia congenita (hyperPP/PMC). PMC with varying degrees of overlap and has been reported in Periodic paralysis was particularly severe, with several association with eight mutations in SCN4A gene (I693T, episodes a day lasting for hours. The onset of episodes T704M, A1156T, T1313M, M1360V, M1370V, R1448C, was unusually early, beginning in the first year of life and M1592V).3–9 While T704M is an important cause of isolated persisting into adult life. The paralytic episodes were hyperPP, this mutation has been only recently described in a refractory to treatment. Patients described minimal single hyperPP/PMC family. As with other SCN4A mutations, paramyotonia, mainly of the eyelids and hands. All there can be marked intrafamilial and interfamilial variability affected family members carried the threonine to in paralytic attack frequency and severity in patients harbour- methionine substitution at codon 704 (T704M) in exon 13 ing T704M.10–12 We report an Italian kindred, in which all of the skeletal muscle voltage gated sodium channel gene patients presented with an unusually severe and homogene- (SCN4A). -
Synergistic Antinociception by the Cannabinoid Receptor Agonist Anandamide and the PPAR-Α Receptor Agonist GW7647
European Journal of Pharmacology 566 (2007) 117–119 www.elsevier.com/locate/ejphar Short communication Synergistic antinociception by the cannabinoid receptor agonist anandamide and the PPAR-α receptor agonist GW7647 Roberto Russo a, Jesse LoVerme b, Giovanna La Rana a, Giuseppe D'Agostino a, Oscar Sasso a, ⁎ Antonio Calignano a, Daniele Piomelli b, a Department of Experimental Pharmacology, University of Naples, Naples, Italy b Department of Pharmacology, 360 MSRII, University of California, Irvine, California 92697-4625, United States Received 9 December 2006; received in revised form 27 February 2007; accepted 6 March 2007 Available online 19 March 2007 Abstract The analgesic properties of cannabinoid receptor agonists are well characterized. However, numerous side effects limit the therapeutic potential of these agents. Here we report a synergistic antinociceptive interaction between the endogenous cannabinoid receptor agonist anandamide and the synthetic peroxisome proliferator-activated receptor-α (PPAR-α) agonist 2-(4-(2-(1-Cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2- methylpropionic acid (GW7647) in a model of acute chemical-induced pain. Moreover, we show that anandamide synergistically interacts with the large-conductance potassium channel (KCa1.1, BK) activator isopimaric acid. These findings reveal a synergistic interaction between the endocannabinoid and PPAR-α systems that might be exploited clinically and identify a new pharmacological effect of the BK channel activator isopimaric acid. © 2007 Elsevier B.V. -
Centipede KCNQ Inhibitor Sstx Also Targets KV1.3
toxins Article Centipede KCNQ Inhibitor SsTx Also Targets KV1.3 Canwei Du 1, Jiameng Li 1, Zicheng Shao 1, James Mwangi 2,3, Runjia Xu 1, Huiwen Tian 1, Guoxiang Mo 1, Ren Lai 1,2,4,* and Shilong Yang 2,4,* 1 College of Life Sciences, Nanjing Agricultural University, Nanjing 210095, Jiangsu, China; [email protected] (C.D.); [email protected] (J.L.); [email protected] (Z.S.); [email protected] (R.X.); [email protected] (H.T.); [email protected] (G.M.) 2 Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences/Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China; [email protected] 3 University of Chinese Academy of Sciences, Beijing 100009, China 4 Sino-African Joint Research Center, Chinese Academy of Science, Wuhan 430074, Hubei, China * Correspondence: [email protected] (R.L.); [email protected] (S.Y.) Received: 27 December 2018; Accepted: 27 January 2019; Published: 1 February 2019 Abstract: It was recently discovered that Ssm Spooky Toxin (SsTx) with 53 residues serves as a key killer factor in red-headed centipede’s venom arsenal, due to its potent blockage of the widely expressed KCNQ channels to simultaneously and efficiently disrupt cardiovascular, respiratory, muscular, and nervous systems, suggesting that SsTx is a basic compound for centipedes’ defense and predation. Here, we show that SsTx also inhibits KV1.3 channel, which would amplify the broad-spectrum disruptive effect of blocking KV7 channels. Interestingly, residue R12 in SsTx extends into the selectivity filter to block KV7.4, however, residue K11 in SsTx replaces this ploy when toxin binds on KV1.3. -
Muscle Channelopathies
Muscle Channelopathies Stanley Iyadurai, MSc PhD MD Assistant Professor of Neurology, Neuromuscular Specialist, OSU, Columbus, OH August 28, 2015 24 F 9 M 18 M 23 F 16 M 8/10 Occasional “Paralytic “Seizures at “Can’t Release Headaches Gait Problems Episodes” Night” Grip” Nausea Few Seconds Few Hours “Parasomnia” “Worse in Winter” Vomiting Debilitating Few Days Full Recovery Full Recovery Video EEG Exercise – Light- Worse Sound- 1-2x/month 1-2x/year Pelvic Red Lobster Thrusting 1-2x/day 3-4/year Dad? Dad? 1-2x/year Dad? Sister Normal Exam Normal Exam Normal Exam Normal Exam Hyporeflexia Normal Exam “Defined Muscles” Photophobia Hyper-reflexia Phonophobia Migraines Episodic Ataxia Hypo Per Paralysis ADNFLE PMC CHANNELOPATHIES DEFINITION Channelopathy: a disease caused by dysfunction of ion channels; either inherited (Mendelian) or acquired/complex (Non-Mendelian, e.g., autoimmune), presenting either in neurologic or non-neurologic fashion CHANNELOPATHY SPECTRUM CHARACTERISTICS Paroxysmal Episodic Intermittent/Fluctuating Bouts/Attacks Between Attacks Patients are Usually Completely Normal Triggers – Hunger, Fatigue, Emotions, Stress, Exercise, Diet, Temperature, or Hormones Muscle Myotonic Disorders Periodic Paralysis MUSCLE CHANNELOPATHIES Malignant Hyperthermia CNS Migraine Episodic Ataxia Generalized Epilepsy with Febrile Seizures Plus Hereditary & Peripheral nerve Acquired Erythromelalgia Congenital Insensitivity to Pain Neuromyotonia NMJ Congenital Myasthenic Syndromes Myasthenia Gravis Lambert-Eaton MS Cardiac Congenital -
Review Article Channelopathies
J Med Genet 2000;37:729–740 729 Review article J Med Genet: first published as 10.1136/jmg.37.10.729 on 1 October 2000. Downloaded from Channelopathies: ion channel defects linked to heritable clinical disorders Ricardo Felix Abstract number of inherited ion channel diseases Electrical signals are critical for the func- named collectively “channelopathies”, caused tion of neurones, muscle cells, and cardiac by mutations in K+,Na+,Ca2+, and Cl- channels myocytes. Proteins that regulate electrical that are known to exist in human and animal signalling in these cells, including voltage models. gated ion channels, are logical sites where Ion channels constitute a class of macromo- abnormality might lead to disease. Ge- lecular protein tunnels that span the lipid netic and biophysical approaches are bilayer of the cell membrane, which allow ions being used to show that several disorders to flow in or out of the cell in a very eYcient result from mutations in voltage gated ion fashion (up to 106 per second). This flow of channels. Understanding gained from ions creates electrical currents (in the order of early studies on the pathogenesis of a 10-12 to 10-10 amperes per channel) large enough group of muscle diseases that are similar to produce rapid changes in the transmem- in their episodic nature (periodic paraly- brane voltage, which is the electrical potential sis) showed that these disorders result diVerence between the cell interior and exte- from mutations in a gene encoding a volt- rior. Inasmuch as Na+ and Ca2+ ions are at age gated Na+ channel. Their characteri- higher concentrations extracellularly than in- sation as channelopathies has served as a tracellularly, openings of Na+ and Ca2+ chan- paradigm for other episodic disorders. -
Transient Compartment-Like Syndrome and Normokalaemic Periodic Paralysis Due to a Cav1.1 Mutation
doi:10.1093/brain/awt300 Brain 2013: 136; 3775–3786 | 3775 BRAIN A JOURNAL OF NEUROLOGY Transient compartment-like syndrome and normokalaemic periodic paralysis due to a Cav1.1 mutation Downloaded from https://academic.oup.com/brain/article/136/12/3775/447564 by guest on 01 October 2021 Chunxiang Fan,1 Frank Lehmann-Horn,1,2 Marc-Andre´ Weber,3,4 Marcin Bednarz,1 James R. Groome,5 Malin K. B. Jonsson6 and Karin Jurkat-Rott1,2 1 Neurophysiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany 2 Rare Disease Centre (ZSE) Ulm and Neuromuscular Disease Centre (NMZ) Ulm, Germany 3 University Hospital of Heidelberg, Department of Diagnostic and Interventional Radiology, Heidelberg, Germany 4 Department of Radiology, German Cancer Research Centre, Heidelberg, Germany 5 Biology Department, Idaho State University, Pocatello, ID, USA 6 Division of Heart and Lungs, University Medical Centre Utrecht, Utrecht, The Netherlands Correspondence to: Karin Jurkat-Rott, Division of Neurophysiology, Ulm University, Albert-Einstein-Allee 11, 89081 Ulm, Germany E-mail: [email protected] We studied a two-generation family presenting with conditions that included progressive permanent weakness, myopathic myopathy, exercise-induced contracture before normokalaemic periodic paralysis or, if localized to the tibial anterior muscle group, transient compartment-like syndrome (painful acute oedema with neuronal compression and drop foot). 23Na and 1H magnetic resonance imaging displayed myoplasmic sodium overload, and oedema. We identified a novel familial Cav1.1 calcium channel mutation, R1242G, localized to the third positive charge of the domain IV voltage sensor. Functional expression of R1242G in the muscular dysgenesis mouse cell line GLT revealed a 28% reduced central pore inward current and a À20 mV shift of the steady-state inactivation curve.