The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Stephen C. Cannon - One of the best experts on this subject based on the ideXlab platform.
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C.,The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation, J.Neurosci
2015Co-Authors: Arie F. Struyk, Kylie A. Scoggan, Dennis E. Bulman, Stephen C. CannonAbstract:Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paraMyotonia con-genita, and Potassium-Aggravated Myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (Hy-poPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated re-cently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca21 channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on acti-vation or fast inactivation but does cause an enhancement o
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the human skeletal muscle na channel mutation r669h associated with hypokalemic periodic paralysis enhances slow inactivation
The Journal of Neuroscience, 2000Co-Authors: Arie F. Struyk, Kylie A. Scoggan, Dennis E. Bulman, Stephen C. CannonAbstract:Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paraMyotonia congenita, and Potassium-Aggravated Myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (HypoPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated recently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca2+ channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on activation or fast inactivation but does cause an enhancement of slow inactivation. R669H channels exhibit an ∼10 mV hyperpolarized shift in the voltage dependence of slow inactivation and a twofold to fivefold prolongation of recovery after prolonged depolarization. In contrast, slow inactivation is often disrupted in HyperPP-associated Na channel mutants. These results demonstrate that, in R669H-associated HypoPP, enhanced slow inactivation does not preclude, and may contribute to, prolonged attacks of weakness and add support to previous evidence implicating the IIS4 voltage sensor in slow-inactivation gating.
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Defective slow inactivation of sodium channels contributes to familial periodic paralysis
Neurology, 1999Co-Authors: Lawrence J. Hayward, Gisela M. Sandoval, Stephen C. CannonAbstract:Objective: To evaluate the effects of missense mutations within the skeletal muscle sodium (Na) channel on slow inactivation (SI) in periodic paralysis and related myotonic disorders. Background: Na channel mutations in hyperkalemic periodic paralysis and the nondystrophic Myotonias interfere with the normally rapid inactivation of muscle Na currents following an action potential. This defect causes persistent inward Na currents that produce muscle depolarization, Myotonia, or onset of weakness. Distinct from fast inactivation is the process called SI, which limits availability of Na channels on a time scale of seconds to minutes, thereby influencing muscle excitability. Methods: Human Na channel cDNAs containing mutations associated with paralytic and nonparalytic phenotypes were transiently expressed in human embryonic kidney cells for whole-cell Na current recording. Extent of SI over a range of conditioning voltages (−120 to +20 mV) was defined as the fraction of Na current that failed to recover within 20 ms at −100 mV. The time course of entry to SI at −30 mV was measured using a conditioning pulse duration of 20 ms to 60 seconds. Recovery from SI at −100 mV was assessed over 20 ms to 10 seconds. Results: The two most common hyperkalemic periodic paralysis (HyperPP) mutations responsible for episodic attacks of weakness or paralysis, T704M and M1592V, showed clearly impaired SI, as we and others have observed previously for the rat homologs of these mutations. In addition, a new paralysis-associated mutant, I693T, with cold-induced weakness, exhibited a comparable defect in SI. However, SI remained intact for both the HyperPP/paraMyotonia congenita (PMC) mutant, A1156T, and the nonparalytic Potassium-Aggravated Myotonia (PAM) mutant, V1589M. Conclusions: SI is defective in a subset of mutant Na channels associated with episodic weakness (HyperPP or PMC) but remains intact for mutants studied so far that cause Myotonia without weakness (PAM).
Arie F. Struyk - One of the best experts on this subject based on the ideXlab platform.
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C.,The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation, J.Neurosci
2015Co-Authors: Arie F. Struyk, Kylie A. Scoggan, Dennis E. Bulman, Stephen C. CannonAbstract:Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paraMyotonia con-genita, and Potassium-Aggravated Myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (Hy-poPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated re-cently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca21 channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on acti-vation or fast inactivation but does cause an enhancement o
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the human skeletal muscle na channel mutation r669h associated with hypokalemic periodic paralysis enhances slow inactivation
The Journal of Neuroscience, 2000Co-Authors: Arie F. Struyk, Kylie A. Scoggan, Dennis E. Bulman, Stephen C. CannonAbstract:Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paraMyotonia congenita, and Potassium-Aggravated Myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (HypoPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated recently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca2+ channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on activation or fast inactivation but does cause an enhancement of slow inactivation. R669H channels exhibit an ∼10 mV hyperpolarized shift in the voltage dependence of slow inactivation and a twofold to fivefold prolongation of recovery after prolonged depolarization. In contrast, slow inactivation is often disrupted in HyperPP-associated Na channel mutants. These results demonstrate that, in R669H-associated HypoPP, enhanced slow inactivation does not preclude, and may contribute to, prolonged attacks of weakness and add support to previous evidence implicating the IIS4 voltage sensor in slow-inactivation gating.
Kylie A. Scoggan - One of the best experts on this subject based on the ideXlab platform.
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C.,The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation, J.Neurosci
2015Co-Authors: Arie F. Struyk, Kylie A. Scoggan, Dennis E. Bulman, Stephen C. CannonAbstract:Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paraMyotonia con-genita, and Potassium-Aggravated Myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (Hy-poPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated re-cently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca21 channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on acti-vation or fast inactivation but does cause an enhancement o
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the human skeletal muscle na channel mutation r669h associated with hypokalemic periodic paralysis enhances slow inactivation
The Journal of Neuroscience, 2000Co-Authors: Arie F. Struyk, Kylie A. Scoggan, Dennis E. Bulman, Stephen C. CannonAbstract:Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paraMyotonia congenita, and Potassium-Aggravated Myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (HypoPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated recently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca2+ channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on activation or fast inactivation but does cause an enhancement of slow inactivation. R669H channels exhibit an ∼10 mV hyperpolarized shift in the voltage dependence of slow inactivation and a twofold to fivefold prolongation of recovery after prolonged depolarization. In contrast, slow inactivation is often disrupted in HyperPP-associated Na channel mutants. These results demonstrate that, in R669H-associated HypoPP, enhanced slow inactivation does not preclude, and may contribute to, prolonged attacks of weakness and add support to previous evidence implicating the IIS4 voltage sensor in slow-inactivation gating.
Dennis E. Bulman - One of the best experts on this subject based on the ideXlab platform.
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C.,The human skeletal muscle Na channel mutation R669H associated with hypokalemic periodic paralysis enhances slow inactivation, J.Neurosci
2015Co-Authors: Arie F. Struyk, Kylie A. Scoggan, Dennis E. Bulman, Stephen C. CannonAbstract:Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paraMyotonia con-genita, and Potassium-Aggravated Myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (Hy-poPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated re-cently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca21 channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on acti-vation or fast inactivation but does cause an enhancement o
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the human skeletal muscle na channel mutation r669h associated with hypokalemic periodic paralysis enhances slow inactivation
The Journal of Neuroscience, 2000Co-Authors: Arie F. Struyk, Kylie A. Scoggan, Dennis E. Bulman, Stephen C. CannonAbstract:Missense mutations of the human skeletal muscle voltage-gated Na channel (hSkM1) underlie a variety of diseases, including hyperkalemic periodic paralysis (HyperPP), paraMyotonia congenita, and Potassium-Aggravated Myotonia. Another disorder of sarcolemmal excitability, hypokalemic periodic paralysis (HypoPP), which is usually caused by missense mutations of the S4 voltage sensors of the L-type Ca channel, was associated recently in one family with a mutation in the outermost arginine of the IIS4 voltage sensor (R669H) of hSkM1 (Bulman et al., 1999). Intriguingly, an arginine-to-histidine mutation at the homologous position in the L-type Ca2+ channel (R528H) is a common cause of HypoPP. We have studied the gating properties of the hSkM1-R669H mutant Na channel experimentally in human embryonic kidney cells and found that it has no significant effects on activation or fast inactivation but does cause an enhancement of slow inactivation. R669H channels exhibit an ∼10 mV hyperpolarized shift in the voltage dependence of slow inactivation and a twofold to fivefold prolongation of recovery after prolonged depolarization. In contrast, slow inactivation is often disrupted in HyperPP-associated Na channel mutants. These results demonstrate that, in R669H-associated HypoPP, enhanced slow inactivation does not preclude, and may contribute to, prolonged attacks of weakness and add support to previous evidence implicating the IIS4 voltage sensor in slow-inactivation gating.
Frank Lehmann-horn - One of the best experts on this subject based on the ideXlab platform.
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SHORT REPORT Familial cramp due to Potassium-Aggravated Myotonia
2016Co-Authors: Richard W. Orrell, Frank Lehmann-horn, Karin Jurkat-rott, Russell J.m. LaneAbstract:Clinical, electrophysiological, and mo-lecular genetic features were investigated in two patients from a family a with domi-nantly inherited myotonic disease, char-acterised by painful cramps, stiVness without weakness, fluctuation of symp-toms, and cold sensitivity. A reduction in amplitude of the compound muscle action potential was demonstrated on cooling and administration of potassium, alth-ough no clinical exacerbation was seen. A heterozygote mutation Val1589Met was identified in the á-subunit of the skeletal muscle sodium channel gene in both patients, consistent with the diagnosis of Potassium-Aggravated Myotonia. The phenotype in this family is much milder than that previously described in another family with a mutation at this site
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Muscle Na+ channelopathies MRI detects intracellular 23Na accumulation during episodic weakness
Neurology, 2006Co-Authors: Marc-andré Weber, Karin Jurkat-rott, Sonia Nielles-vallespin, Marco Essig, H.-u. Kauczor, Frank Lehmann-hornAbstract:Background: Muscle channelopathies such as paraMyotonia, hyperkalemic periodic paralysis, and Potassium-Aggravated Myotonia are caused by gain-of-function Na + channel mutations. Methods: Implementation of a three-dimensional radial 23 Na magnetic resonance (MR) sequence with ultra-short echo times allowed the authors to quantify changes in the total muscular 23 Na signal intensity. By this technique and T2-weighted 1 H MRI, the authors studied whether the affected muscles take up Na + and water during episodes of myotonic stiffness or of cold- or exercise-induced weakness. Results: A 22% increase in the 23 Na signal intensity and edema-like changes on T2-weighted 1 H MR images were associated with cold-induced weakness in all 10 paraMyotonia patients; signal increase and weakness disappeared within 1 day. A 10% increase in 23 Na, but no increase in the T2-weighted 1 H signal, occurred during cold- or exercise-induced weakness in seven hyperkalemic periodic paralysis patients, and no MR changes were observed in controls or exercise-induced stiffness in six Potassium-Aggravated Myotonia patients. Measurements on native muscle fibers revealed provocation-induced, intracellular Na + accumulation and membrane depolarization by −41 mV for paraMyotonia, by −30 mV for hyperkalemic periodic paralysis, and by −20 mV for Potassium-Aggravated Myotonia. The combined in vivo and in vitro approach showed a close correlation between the increase in 23 Na MR signal intensity and the membrane depolarization (r = 0.92). Conclusions: The increase in the total 23 Na signal intensity reflects intracellular changes, the cold-induced Na + shifts are greatest and osmotically relevant in paraMyotonia patients, and even osmotically irrelevant Na + shifts can be detected by the implemented 23 Na MR technique.
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Chapter 23 Skeletal muscle channelopathies: Myotonias, periodic paralyses and malignant hyperthermia
Handbook of Clinical Neurophysiology, 2003Co-Authors: Frank Lehmann-horn, Holger Lerche, Karin Jurkat-rottAbstract:Publisher Summary This chapter discusses the channelopathies of skeletal muscle. Membrane excitability is regulated by voltage-gated ion channels that are essential for the stabilization of the resting membrane potential and the generation of the action potential. Ion channels are involved in the pathogenesis of diseases of skeletal muscle. Channelopathies are defined as episodically recurring disorders caused by the pathology of an ion-channel function. Clinically, skeletal muscle ion channelopathies appear as episodes of muscle stiffness or weakness triggered by typical circumstances such as cold, exercise, oral potassium load, or drugs. According to the mode of transmission and potassium sensitivity, there are four forms of Myotonia and paraMyotonia: dominant Myotonia congenita, recessive Myotonia congenita, dominant Potassium-Aggravated Myotonia, and dominant paraMyotonia congenita. Myotonic dystrophy type 1 and myotonic dystrophy type 2 are chronic progressive multisystemic diseases of dominant inheritance. A myotonic reaction prevents the muscle from immediate relaxation that patients experience as muscle stiffness.
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Chapter 8 Sodium channelopathies in skeletal muscle and brain
Advances in Clinical Neurophysiology XV International Congress of Clinical Neurophysiology, 2002Co-Authors: Holger Lerche, Nenad Mitrovic, Karin Jurkat-rott, Frank Lehmann-hornAbstract:Publisher Summary The first so called “channelopathies” identified were skeletal muscle diseases, Myotonias, and hyperkalemic periodic paralysis (HyperPP) that are sodium or chloride channel disorders. In recent years, complementary genetic and electrophysiological investigations led to the continuously growing list of channelopathies. Beside skeletal muscle, the channelopathies affect other excitable tissues, such as heart muscle and the nervous system. Voltage gated sodium channels (VGSCs) are membrane spanning proteins, responsible for the initiation and propagation of action potentials, in nerve and muscle cells. This chapter discusses the pathophysiological concepts of the sodium channelopathies found in skeletal muscle and brain— namely, HyperPP, paraMyotonia congenita (PC), potassium aggravated Myotonia (PAM), hypokalemic periodic paralysis type 2 (HypoPP2), generalized epilepsy, with febrile seizures plus (GEFS + ), and severe myoclonic epilepsy of infancy (SMEI). HyperPP, PC, and PAM are gain-of-function sodium channelopathies of the skeletal muscle. The inactivation defect, common to all mutations, can fully explain the phenotypes of Myotonia and/or paralysis via a slight or strong membrane depolarization, respectively. HypoPP2 is a loss-of-function sodium channelopathy, but the described enhancement of fast and/or slow inactivation can only explain a part of the pathophysiological features of this disease.
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A human muscle Na+ channel mutation in the voltage sensor IV/S4 affects channel block by the pentapeptide KIFMK
The Journal of Physiology, 1999Co-Authors: W. Peter, Frank Lehmann-horn, Nenad Mitrovic, M. Schiebe, Holger LercheAbstract:Whole cell patch clamping of transfected HEK293 cells was used to examine the effects of a pentapeptide (KIFMK) containing the proposed inactivation particle of the Na+ channel on two mutations causing Myotonia. One mutation (R1448P) is located in the voltage sensor IV/S4, and the other one (G1306E) near the postulated inactivation gate within the III-IV linker. In the absence of peptide, currents of wild-type (WT) and mutant human muscle Na+ channels decayed monoexponentially with inactivation time constants that were 5-fold (R1448P) and 3-fold (G1306E) larger for the mutants. Upon intracellular application of KIFMK (0·3-1 mM) the current decay became biexponential with an additional fast decaying component that increased in amplitude with depolarization. Furthermore, the peptide induced large tail currents upon repolarization, indicating that KIFMK prevents inactivation by blocking open Na+ channels. The peak of this tail current decreased only slowly with depolarizations of increasing duration. The voltage dependence of this decline indicated that the dissociation rate of the charged peptide decreased with depolarization. Increased external [Na+] ([Na+]e) antagonized block by KIFMK, consistent with a pore-blocking mechanism. The results are discussed with regard to a three-state model for one open, an absorbing inactivated and one blocked state with voltage-dependent on- and off-rates for peptide binding. The peptide had qualitatively similar effects on WT and both mutants, indicating that the freely diffusible peptide accelerates the current decay in all three clones. However, for the R1448P mutation the affinity for KFIMK was decreased and the voltage dependence of peptide block was changed in a similar way to the voltage dependence of inactivation. These data suggest that the mutation R1448P affects the voltage-dependent formation of a receptor site for both the inactivation particle and KIFMK. Voltage-gated Na+ channels are the basis for the generation and conduction of action potentials in nerve and muscle cells. Na+ channels open briefly upon depolarization and then close to a fast inactivated state from which they reopen only rarely. Thus, fast inactivation limits the duration of an action potential and initiates its repolarizing phase. The α-subunit constitutes both the gating and permeation machinery of the Na+ channel, and consists of four homologous domains (I-IV), each with six transmembrane segments (S1-S6). The S4 segments contain positively charged residues conferring voltage dependence to the channel protein, the S5-S6 loops contribute to the ion channel pore, and the intracellular loop linking domains III and IV (LIII-IV) contains structures required for channel inactivation (for a review, see Catterall, 1995). A current model for the molecular mechanism of fast Na+ channel inactivation proposes that an intracellular particle within LIII-IV consisting of three hydrophobic amino acids (isoleucine, phenylalanine and methionine; IFM) occludes the channel pore in a hinged-lid fashion (West et al. 1992). Further evidence for IFM forming a pore-closing particle comes from a recent study of Kellenberger et al. (1996). These authors showed that a cysteine substituted for the phenylalanine of IFM is only accessible for the thiol reagent MTSET in the hyperpolarized state, when channels are not inactivated. Vedantham & Cannon (1998) further showed that the voltage dependence of the reaction rate for MTSET with this cysteine mutation fits perfectly the steady-state inactivation curve of the channel. A pentapeptide containing the IFM motif (lysine-isoleucine-phenylalanine-methionine-lysine = KIFMK) blocks a non-inactivating mutant lacking the natural IFM; other peptides not containing IFM, such as KIQMK or KAFAK, do not have this effect (Eaholtz et al. 1994). These data suggest a common binding site for the natural IFM and the peptide. Tang and coworkers tested the effects of KIFMK on two different, slowly inactivating Na+ channel mutants and concluded that the peptide is an open channel blocker acting in a different way from normal inactivation (Tang et al. 1996). Whereas Eaholtz and colleagues found a voltage-dependent association and a voltage-independent dissociation rate for KIFMK binding (Eaholtz et al. 1998), Tang et al. (1996) calculated voltage-independent rate constants for both binding and unbinding of the peptide. In order to investigate the mechanism of action of KIFMK further, we chose two Myotonia-causing mutations in different regions of the channel protein; both slow inactivation to a similar extent, but probably by different mechanisms. One mutation, glycine-1306-glutamate (G1306E), causes Potassium-Aggravated Myotonia and is located only four amino acids away from IFM within LIII-IV. This mutation might slow inactivation by hindering the movement of the putative inactivation particle (Lerche et al. 1993; Mitrovic et al. 1995; Hayward et al. 1996). The other mutation, arginine-1448-proline (R1448P), causes paraMyotonia congenita and is located at the extracellular surface of the voltage sensor IV/S4 (Wang et al. 1995; Lerche et al. 1996; Featherstone et al. 1998; Mitrovic et al. 1999; for a review of the Na+ channelopathies, see Lehmann-Horn & Rudel, 1996). This voltage sensor plays an important role in the coupling of inactivation to activation (Chahine et al. 1994) and its outward movement (Yang et al. 1996) might therefore initiate the formation of a receptor site for the inactivation particle. Thus, R1448P should slow inactivation by affecting the conformation of the receptor for the inactivation gate, whereas G1306E should hinder the gate itself. Hence, if the natural inactivation gate and the pentapeptide KIFMK had the same binding site, R1448P but not G1306E should affect channel block by KIFMK. Indeed, we found a difference in the affinity and voltage dependence of KIFMK block of the R1448P mutation resembling the altered voltage dependence of inactivation of this mutation, whereas KIFMK block for G1306E and wild-type (WT) channels was similar. In addition, our results complement the aforementioned studies (Eaholtz et al. 1994, 1998; Tang et al. 1996) and provide new insight into the mechanism of peptide block.