Action potential conduction and sodium channel content in the optic nerve of the myelin-deficient rat

Some mutations of the sodium channel gene NaV1.5 are multifunctional, causing combinations of LQTS, Brugada syndrome and progressive cardiac conduction system disease (PCCD). The combination of Brugada syndrome and PCCD is uncommon, although they both result from a reduction in the sodium current. We hypothesize that slow conduction is sufficient to cause S-T segment elevation and undertook a combined experimental and theoretical study to determine whether conduction slowing alone can produce the Brugada phenotype. Deletion of lysine 1479 in one of two positively charged clusters in the III/IV inter-domain linker causes both syndromes. We have examined the functional effects of this mutation using heterologous expression of the wild-type and mutant sodium channel in HEK-293-EBNA cells. We show that ΔK1479 shifts the potential of half-activation, V1/2m, to more positive potentials ( V1/2m = −36.8 ± 0.8 and −24.5 ± 1.3 mV for the wild-type and ΔK1479 mutant respectively, n = 11, 10). The depolarizing shift increases the extent of depolarization required for activation. The potential of half-inactivation, V1/2h, is also shifted to more positive potentials ( V1/2h = −85 ± 1.1 and −79.4 ± 1.2 mV for wild-type and ΔK1479 mutant respectively), increasing the fraction of channels available for activation. These shifts are quantitatively the same as a mutation that produces PCCD only, G514C. We incorporated experimentally derived parameters into a model of the cardiac action potential and its propagation in a one dimensional cable (simulating endo-, mid-myocardial and epicardial regions). The simulations show that action potential and ECG changes consistent with Brugada syndrome may result from conduction slowing alone; marked repolarization heterogeneity is not required. The findings also suggest how Brugada syndrome and PCCD which both result from loss of sodium channel function are sometimes present alone and at other times in combination.

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Nicotinic Acetylcholine Receptors in Mouse and Rat Optic Nerves

Journal of Neurophysiology ◽

10.1152/jn.00769.2003 ◽

2004 ◽

Vol 91 (2) ◽

pp. 1025-1035 ◽

Cited By ~ 20

Author(s):

Chuan-Li Zhang ◽

Yakov Verbny ◽

Sameh A. Malek ◽

Peter K. Stys ◽

Shing Yan Chiu

Keyword(s):

Optic Nerve ◽

Action Potential ◽

Nicotinic Acetylcholine Receptors ◽

Compound Action Potential ◽

Calcium Response ◽

Nicotinic Acetylcholine ◽

Optic Nerves ◽

Activity Dependent ◽

Calcium Elevation ◽

Compound Action

Receptor-mediated calcium signaling in axons of mouse and rat optic nerves was examined by selectively staining the axonal population with a calcium indicator. Nicotine (1-50 μM) induced an axonal calcium elevation that was eliminated when calcium was removed from the bath, suggesting that nicotine induces calcium influx into axons. The nicotine response was blocked by d-tubocurarine and mecamylamine but not α-bungarotoxin, indicating the presence of calcium permeable, non-α7 nicotinic acetylcholine receptor (nAChR) subtype. Agonist efficacy order for eliciting the axonal nAChR calcium response was cytisine ∼ nicotine >> acetylcholine. The nicotine-mediated calcium response was attenuated during the process of normal myelination, decreasing by approximately 10-fold from P1 (premyelinated) to P30 (myelinated). Nicotine also caused a rapid reduction in the compound action potential in neonatal optic nerves, consistent with a shunting of the membrane after opening of the nonspecific cationic nicotinic channels. Voltagegated calcium channels contributed little to the axonal calcium elevation during nAChR activation. During repetitive stimulations, the compound action potential in neonatal mouse optic nerves underwent a gradual reduction in amplitude that could be partially prevented by d-tubocurarine, suggesting an activity-dependent release of acetylcholine that activates axonal AChRs. We conclude that mammalian optic nerve axons express nAChRs and suggest that these receptors are activated in an activity-dependent fashion during optic nerve development to modulate axon excitability and biology.

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Macromolecular structure of axon membrane and action potential conduction in myelin deficient and myelin deficient heterozygote rat optic nerves

Journal of Neurocytology ◽

10.1007/bf01188436 ◽

1990 ◽

Vol 19 (1) ◽

pp. 11-28 ◽

Cited By ~ 13

Author(s):

S. G. Waxman ◽

J. A. Black ◽

I. D. Duncan ◽

B. R. Ransom

Keyword(s):

Action Potential ◽

Macromolecular Structure ◽

Axon Membrane ◽

Optic Nerves ◽

Myelin Deficient

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Ion Channel and Structural Remodeling in Obesity-Mediated Atrial Fibrillation

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.120.008296 ◽

2020 ◽

Vol 13 (8) ◽

Cited By ~ 1

Author(s):

Mark D. McCauley ◽

Liang Hong ◽

Arvind Sridhar ◽

Ambili Menon ◽

Srikanth Perike ◽

...

Keyword(s):

Atrial Fibrillation ◽

Action Potential ◽

Ion Channel ◽

Sodium Channel ◽

Action Potential Duration ◽

Obese Mice ◽

Atrial Fibrosis ◽

Structural Remodeling ◽

Cardiac Sodium Channel ◽

Channel Expression

Background: Epidemiological studies have established obesity as an independent risk factor for atrial fibrillation (AF), but the underlying pathophysiological mechanisms remain unclear. Reduced cardiac sodium channel expression is a known causal mechanism in AF. We hypothesized that obesity decreases Nav1.5 expression via enhanced oxidative stress, thus reducing I Na , and enhancing susceptibility to AF. Methods: To elucidate the underlying electrophysiological mechanisms a diet-induced obese mouse model was used. Weight, blood pressure, glucose, F 2 -isoprostanes, NOX2 (NADPH oxidase 2), and PKC (protein kinase C) were measured in obese mice and compared with lean controls. Invasive electrophysiological, immunohistochemistry, Western blotting, and patch clamping of membrane potentials was performed to evaluate the molecular and electrophysiological phenotype of atrial myocytes. Results: Pacing-induced AF in 100% of diet-induced obese mice versus 25% in controls ( P <0.01) with increased AF burden. Cardiac sodium channel expression, I Na and atrial action potential duration were reduced and potassium channel expression (Kv1.5) and current ( I Kur ) and F 2 -isoprostanes, NOX2, and PKC-α/δ expression and atrial fibrosis were significantly increased in diet-induced obese mice as compared with controls. A mitochondrial antioxidant reduced AF burden, restored I Na , I Ca,L , I Kur , action potential duration, and reversed atrial fibrosis in diet-induced obese mice as compared with controls. Conclusions: Inducible AF in obese mice is mediated, in part, by a combined effect of sodium, potassium, and calcium channel remodeling and atrial fibrosis. Mitochondrial antioxidant therapy abrogated the ion channel and structural remodeling and reversed the obesity-induced AF burden. Our findings have important implications for the management of obesity-mediated AF in patients. Graphic Abstract: A graphic abstract is available for this article.

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Optic nerve tissue sections derived from myelin-deficient mutant mice as culture substrata for fibroblast adhesion and spreading

Experimental Cell Research ◽

10.1016/0014-4827(91)90142-h ◽

1991 ◽

Vol 194 (1) ◽

pp. 135-138 ◽

Cited By ~ 2

Author(s):

Ivar J. Kljavin ◽

Roger D. Madison ◽

Thomas A. Reh

Keyword(s):

Optic Nerve ◽

Mutant Mice ◽

Nerve Tissue ◽

Deficient Mutant ◽

Tissue Sections ◽

Fibroblast Adhesion ◽

Myelin Deficient

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Frequency- and voltage-dependent effects of disopyramide in canine Purkinje fibers

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y89-115 ◽

1989 ◽

Vol 67 (7) ◽

pp. 710-721 ◽

Cited By ~ 2

Author(s):

Matthew A. Flemming ◽

Betty I. Sasyniuk

Keyword(s):

Potassium Channels ◽

Action Potential ◽

Sodium Channel ◽

Action Potential Duration ◽

Refractory Period ◽

Drug Effect ◽

Effective Refractory Period ◽

Slow Inactivation ◽

Purkinje Fibers ◽

Rate Dependent

The voltage- and frequency-dependent blocking actions of disopyramide were assessed in canine Purkinje fibers within the framework of concentrations, membrane potentials, and heart rates which have relevance to the therapeutic actions of this drug. [Formula: see text] was used to assess the magnitude of sodium channel block. Disopyramide produced a concentration- and rate-dependent increase in the magnitude and kinetics of [Formula: see text] depression. Effects on activation time (used as an estimate of drug effect on conduction) were exactly analogous to effects on [Formula: see text]. A concentration-dependent increase in tonic block was also observed. Despite significant increases in tonic block at more depolarized potentials, rate-dependent block increased only marginally with membrane potential over the range of potentials in which propagated action potentials occur. Increases in extracellular potassium concentration accentuated drug effect on [Formula: see text] but attenuated drug effect on action potential duration. Recovery from rate-dependent block followed two exponential processes with time constants of 689 ± 535 ms and 15.7 ± 2.7 s. The latter component represents dissociation of drug from its binding site and the former probably represents recovery from slow inactivation. A concentration-dependent increase in the amplitude of the first component suggested that disopyramide may promote slow inactivation. There was less than 5% recovery from block during intervals equivalent to clinical diastole. Thus, depression of beats of all degrees of prematurity was similar to that of basic drive beats. Prolongation of action potential duration by therapeutic concentrations of drug following a long quiescent interval was minimal. However, profound lengthening of action potential duration occurred following washout of drug effect at a time when [Formula: see text] depression had reverted to normal, suggesting that binding of disopyramide to potassium channels may not be readily reversed. Variable effects on action potential duration may thus be attributed to a block of the window current flowing during the action potential being partially or over balanced by block of potassium channels. Purkinje fiber refractoriness was prolonged in a frequency-dependent manner. Disopyramide did not significantly alter the effective refractory period of basic beats but did increase the effective refractory period of sequential tightly coupled extra stimuli. The results can account for the antiarrhythmic actions of disopyramide during a rapid tachycardia and prevention of its initiation by programmed electrical stimulation.Key words: action potential duration, effective refractory period, upstroke velocity, conduction, rate of sodium channel unblocking.

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