Role of Ca<sup>2+</sup> in injury-induced changes in sodium current in rat skeletal muscle

Filatov, Gregory; Pinter, Martin J.; Rich, Mark M.

doi:10.1152/ajpcell.00021.2009

Cited by 8 publications

(9 citation statements)

References 47 publications

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“…Thirdly, the present findings directly confirm previous in vitro suggestions that the resulting increased [Ca 2+ ] i may then inhibit Nav1.4 function in intact skeletal myocytes in situ 25,27 in common with its action on cardiac Nav1.5 4,58 . Nav1.4 and Nav1.5 isoforms possess similar amino acid sequences consistent with such multiple structural and functional homologies 13 .…”

Section: Discussionsupporting

confidence: 90%

“…Furthermore, homologies between Nav1.4 and Nav1.5 are compatible with similarities in functional properties 13 . In preliminary reports, Nav1.4 function was inhibited by Ca 2+ entry through neighbouring Ca 2+ channels, photorelease of caged Ca 2+ in transfected HEK293 cells and skeletal muscle cell lines 25 , and following release of mitochondrial Ca 2+ in murine skeletal muscle fibres 27 . CaM overexpression similarly negatively shifted steady-state voltage-dependences of Nav1.4 inactivation.…”

Section: Introductionmentioning

confidence: 94%

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Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3′,5′-adenosine monophosphate (Epac) in murine skeletal muscle

Matthews

Tan

Shoesmith

et al. 2019

Sci Rep

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We investigated effects of pharmacological triggering of exchange protein directly activated by cyclic-3′,5′-adenosine monophosphate (Epac) on Nav1.4 currents from intact murine (C67BL6) skeletal muscle fibres for the first time. This employed a loose patch clamp technique which examined ionic currents in response to superimposed 10-ms V1 steps to varying degrees of depolarisation, followed by V2 steps to a fixed, +100 mV depolarisation relative to resting membrane potential following 40 mV hyperpolarising prepulses of 50 ms duration. The activation and inactivation properties of the resulting Na+ membrane current densities revealed reduced maximum currents and steepnesses in their voltage dependences after addition of the Epac activator 8-(4-chlorophenylthio)adenosine-3′,5′-cyclic monophosphate (1 µM) to the bathing Krebs-Henseleit solutions. Contrastingly, voltages at half-maximal current and timecourses of currents obtained in response to the V1 depolarising steps were unchanged. These effects were abolished by further addition of the RyR-inhibitor dantrolene (10 µM). In contrast, challenge by dantrolene alone left both currents and their parameters intact. These effects of Epac activation in inhibiting skeletal muscle, Nav1.4, currents, complement similar effects previously reported in the homologous Nav1.5 in murine cardiomyocytes. They are discussed in terms of a hypothesis implicating Epac actions in increasing RyR-mediated SR Ca2+ release resulting in a Ca2+-mediated inhibition of Nav1.4. The latter effect may form the basis for Ca2+-dependent Na+ channel dysregulation in SCN4A channelopathies associated with cold- and K+-aggravated myotonias.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 94%

Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3′,5′-adenosine monophosphate (Epac) in murine skeletal muscle

Matthews

Tan

Shoesmith

et al. 2019

Sci Rep

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“…Therefore, positive and negative potentials applied within the pipette respectively hyperpolarise and depolarise the membrane potential of the patch relative to the cell resting membrane potential (RMP). In this report, the signs of the voltage steps are inverted and membrane potentials expressed relative to RMP, a convention adopted by previous papers using this technique 12,13,20,26 . The Ag/AgCl electrode within the pipette both measured the intra-pipette potential relative to the ground reference potential of the bath and passed the clamp current.…”

Section: Methodsmentioning

confidence: 99%

Ryanodine receptor modulation by caffeine challenge modifies Na+ current properties in intact murine skeletal muscle fibres

Sarbjit-Singh

Matthews

Huang

2020

Sci Rep

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We investigated effects of the ryanodine receptor (RyR) modulator caffeine on Na + current (I na ) activation and inactivation in intact loose-patch clamped murine skeletal muscle fibres subject to a double pulse procedure. I na activation was examined using 10-ms depolarising, V 1 , steps to varying voltages 0-80 mV positive to resting membrane potential. The dependence of the subsequent, I na inactivation on V 1 was examined by superimposed, V 2 , steps to a fixed depolarising voltage. Currentvoltage activation and inactivation curves indicated that adding 0.5 and 2 mM caffeine prior to establishing the patch seal respectively produced decreased (within 1 min) and increased (after ~2 min) peak I na followed by its recovery to pretreatment levels (after ~40 and ~30 min respectively). These changes accompanied negative shifts in the voltage dependence of I na inactivation (within 10 min) and subsequent superimposed positive activation and inactivation shifts, following 0.5 mM caffeine challenge. In contrast, 2 mM caffeine elicited delayed negative shifts in both activation and inactivation. These effects were abrogated if caffeine was added after establishing the patch seal or with RyR block by 10 μM dantrolene. These effects precisely paralleled previous reports of persistently (~10 min) increased cytosolic [Ca 2+ ] with 0.5 mM, and an early peak rapidly succeeded by persistently reduced [Ca 2+ ] likely reflecting gradual RyR inactivation with ≥1.0 mM caffeine. The latter findings suggested inhibitory effects of even resting cytosolic [Ca 2+ ] on I na . They suggest potentially physiologically significant negative feedback regulation of RyR activity on Na v 1.4 properties through increased or decreased local cytosolic [Ca 2+ ], Ca 2+ -calmodulin and FKBP12.Skeletal muscle excitation-contraction coupling involves triggering of a Na v 1.4 mediated action potential. This is detected by voltage-dependent transverse tubular Ca v 1.1 that undergoes transitions resulting in an allosterically-activated ryanodine receptor (RyR) mediated release of sarcoplasmic reticular (SR) Ca 2+ thereby increasing cytosolic free Ca 2+ concentration, [Ca 2+ ] i , Recent findings have been suggestive of feedback mechanisms through which downstream events in this feedforward sequence might conversely affect Na v 1.4 function. However, many of these reports provided structural rather than functional evidence, or involved experiments in cell lines or isolated cultured cells. They thus provide necessary rather than sufficient evidence for the actual operation of Ca 2+ mediated feedback mechanisms in working muscle in vivo. Few available reports examined the existence and properties of RyR-mediated feedback actions on Na v 1.4 function in intact in situ skeletal myocytes particularly those directly targeting the RyR mediated Ca 2+ release process.First, Na v 1.4 possesses several potential Ca 2+ and calmodulin (CaM) binding or modulation sites. These include: (a) one or more Ca 2+ -binding C-terminal EF-like hand motifs 1 ; (b) a C-terminal i...

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“…One possibility is that Na ϩ currents are especially sensitive to cell sickness/injury. In studies in both skeletal muscle and axons, it appears that damage triggers a hyperpolarized shift in the voltage dependence of the Na ϩ current activation and inactivation as well as a reduction in maximal current density (72,195,494). In injured cells with a depolarized resting potential, a hyperpolarized shift in the voltage dependence of inactivation would result in increased channel inactivation to reduce excitability.…”

Section: Are Electrically Active Tissues Other Than Skeletal Muscle Amentioning

confidence: 99%

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

Friedrich

Reid

Berghe

et al. 2015

Physiological Reviews

300

329

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Critical illness polyneuropathies (CIP) and myopathies (CIM) are common complications of critical illness. Several weakness syndromes are summarized under the term intensive care unit-acquired weakness (ICUAW). We propose a classification of different ICUAW forms (CIM, CIP, sepsis-induced, steroid-denervation myopathy) and pathophysiological mechanisms from clinical and animal model data. Triggers include sepsis, mechanical ventilation, muscle unloading, steroid treatment, or denervation. Some ICUAW forms require stringent diagnostic features; CIM is marked by membrane hypoexcitability, severe atrophy, preferential myosin loss, ultrastructural alterations, and inadequate autophagy activation while myopathies in pure sepsis do not reproduce marked myosin loss. Reduced membrane excitability results from depolarization and ion channel dysfunction. Mitochondrial dysfunction contributes to energy-dependent processes. Ubiquitin proteasome and calpain activation trigger muscle proteolysis and atrophy while protein synthesis is impaired. Myosin loss is more pronounced than actin loss in CIM. Protein quality control is altered by inadequate autophagy. Ca 2ϩ dysregulation is present through altered Ca 2ϩ homeostasis. We highlight clinical hallmarks, trigger factors, and potential mechanisms from human studies and animal models that allow separation of risk factors that may trigger distinct mechanisms contributing to weakness. During critical illness, altered inflammatory (cytokines) and metabolic pathways deteriorate muscle function. ICUAW prevention/treatment is limited, e.g., tight glycemic control, delaying nutrition, and early mobilization. Future challenges include identification of primary/secondary events during the time course of critical illness, the interplay between membrane excitability, bioenergetic failure and differential proteolysis, and finding new therapeutic targets by help of tailored animal models.

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Role of Ca²⁺ in injury-induced changes in sodium current in rat skeletal muscle

Abstract: Filatov GN, Pinter MJ, Rich MM. Role of Ca 2ϩ in injuryinduced changes in sodium current in rat skeletal muscle.

Cited by 8 publications

References 47 publications

Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3′,5′-adenosine monophosphate (Epac) in murine skeletal muscle

Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3′,5′-adenosine monophosphate (Epac) in murine skeletal muscle

Ryanodine receptor modulation by caffeine challenge modifies Na+ current properties in intact murine skeletal muscle fibres

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

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Role of Ca2+ in injury-induced changes in sodium current in rat skeletal muscle

Abstract: Filatov GN, Pinter MJ, Rich MM. Role of Ca 2ϩ in injuryinduced changes in sodium current in rat skeletal muscle.

Cited by 8 publications

References 47 publications

Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3′,5′-adenosine monophosphate (Epac) in murine skeletal muscle

Sodium current inhibition following stimulation of exchange protein directly activated by cyclic-3′,5′-adenosine monophosphate (Epac) in murine skeletal muscle

Ryanodine receptor modulation by caffeine challenge modifies Na+ current properties in intact murine skeletal muscle fibres

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

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Product

Resources

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Role of Ca²⁺ in injury-induced changes in sodium current in rat skeletal muscle