A Negative Slope Conductance of the Persistent Sodium Current Prolongs Subthreshold Depolarizations

After chronic spinal cord injury motoneurons exhibit large plateau potentials (sustained depolarizations triggered by brief inputs) that play a primary role in the development of muscle spasms and spasticity (Bennett et al. 2001a , b ). The present study examined the voltage-gated persistent inward currents (PICs) underlying these plateaus. Adult rats were spinalized at the S2 sacral spinal level and after 2 mo, when spasticity developed, intracellular recordings were made from motoneurons below the injury. For recording, the whole sacrocaudal spinal cord was removed and maintained in vitro in normal artificial cerebral spinal fluid (nACSF), without application of neuromodulators. During a slow triangular voltage-clamp command (ramp) a PIC was activated with a threshold of –54.2 ± 4.8 mV (similar to plateau threshold), with a peak current of 2.88 ± 0.95 nA and produced a pronounced negative-slope region in the V–I relation. This PIC was in part mediated by Cav1.3 L-type calcium channels because it was low threshold and significantly reduced by 10 to 20 μM nimodipine or 400 μM Cd2+. The PIC that remained during a calcium channel blockade (in Cd2+) was completely and rapidly blocked by tetrodotoxin (TTX; 0.5 to 2 μM), and thus was a TTX-sensitive persistent sodium current. This persistent sodium current was activated rapidly about 7 mV below the spike threshold (spike threshold –46.1 ± 4.5 mV), contributed approximately 1/2 of the initial peak of the total PIC, inactivated partly to contribute only approximately 1/3 of the sustained PIC (at 5 to 10 s), and deactivated rapidly with hyperpolarization (<50 ms). When TTX was added to the bath first, the nimodipine-sensitive persistent calcium current (L-type) was seen in isolation; it was slowly activated (>250 ms), had a low but variable threshold (either slightly above or below the spike threshold), contributed the other approximately 1/2 of the initial peak of the total PIC (before TTX), did not usually inactivate with time (contributed approximately two-thirds of the sustained PIC), and deactivated slowly with hyperpolarization to rest (in >300 ms). In summary, low-threshold persistent calcium (Cav1.3) and sodium currents spontaneously develop in motoneurons of chronic spinal rats and these enable large, rapidly activated plateaus that ultimately lead to spasticity.

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Muscarinic Enhancement of Persistent Sodium Current Synchronizes Striatal Medium Spiny Neurons

Journal of Neurophysiology ◽

10.1152/jn.00134.2009 ◽

2009 ◽

Vol 102 (2) ◽

pp. 682-690 ◽

Cited By ~ 20

Author(s):

Luis Carrillo-Reid ◽

Fatuel Tecuapetla ◽

Nicolas Vautrelle ◽

Adán Hernández ◽

Ramiro Vergara ◽

...

Keyword(s):

Sodium Current ◽

Network Dynamics ◽

Receptor Activation ◽

Procedural Memory ◽

Negative Slope ◽

Medium Spiny Neurons ◽

Persistent Sodium Current ◽

Intrinsic Properties ◽

Bistable Behavior ◽

Spiny Neurons

Network dynamics denoted by synchronous firing of neuronal pools rely on synaptic interactions and intrinsic properties. In striatal medium spiny neurons, N-methyl-d-aspartate (NMDA) receptor activation endows neurons with nonlinear capabilities by inducing a negative-slope conductance region (NSCR) in the current–voltage relationship. Nonlinearities underlie associative learning, procedural memory, and the sequential organization of behavior in basal ganglia nuclei. The cholinergic system modulates the function of medium spiny projection neurons through the activation of muscarinic receptors, increasing the NMDA-induced NSCR. This enhancement is reflected as a change in the NMDA-induced network dynamics, making it more synchronous. Nevertheless, little is known about the contribution of intrinsic properties that promote this activity. To investigate the mechanisms underlying the cholinergic modulation of bistable behavior in the striatum, we used whole cell and calcium-imaging techniques. A persistent sodium current modulated by muscarinic receptor activation participated in the enhancement of the NSCR and the increased network synchrony. These experiments provide evidence that persistent sodium current generates bistable behavior in striatal neurons and contributes to the regulation of synchronous network activity. The neuromodulation of bistable properties could represent a cellular and network mechanism for cholinergic actions in the striatum.

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Faculty Opinions recommendation of Molecular determinants for modulation of persistent sodium current by G-protein betagamma subunits.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1025012.294762 ◽

2005 ◽

Author(s):

Patrick Delmas

Keyword(s):

G Protein ◽

Sodium Current ◽

Persistent Sodium Current ◽

Molecular Determinants ◽

Betagamma Subunits

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Sodium Currents in Neurons From the Rostroventrolateral Medulla of the Rat

Journal of Neurophysiology ◽

10.1152/jn.00150.2003 ◽

2003 ◽

Vol 90 (3) ◽

pp. 1635-1642 ◽

Cited By ~ 40

Author(s):

Ilya A. Rybak ◽

Krzysztof Ptak ◽

Natalia A. Shevtsova ◽

Donald R. McCrimmon

Keyword(s):

Sodium Channels ◽

Sodium Current ◽

Cell Voltage ◽

Kinetic Properties ◽

Persistent Sodium Current ◽

Sodium Currents ◽

Bötzinger Complex ◽

Window Current ◽

Bursting Activity

Rapidly inactivating and persistent sodium currents have been characterized in acutely dissociated neurons from the area of rostroventrolateral medulla that included the pre-Bötzinger Complex. As demonstrated in many studies in vitro, this area can generate endogenous rhythmic bursting activity. Experiments were performed on neonate and young rats (P1-15). Neurons were investigated using the whole cell voltage-clamp technique. Standard activation and inactivation protocols were used to characterize the steady-state and kinetic properties of the rapidly inactivating sodium current. Slow depolarizing ramp protocols were used to characterize the noninactivating sodium current. The “window” component of the rapidly inactivating sodium current was calculated using mathematical modeling. The persistent sodium current was revealed by subtraction of the window current from the total noninactivating sodium current. Our results provide evidence of the presence of persistent sodium currents in neurons of the rat rostroventrolateral medulla and determine voltage-gated characteristics of activation and inactivation of rapidly inactivating and persistent sodium channels in these neurons.

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Protease-Activated Receptor-1 Mediates Thrombin-Induced Persistent Sodium Current in Human Cardiomyocytes

Molecular Pharmacology ◽

10.1124/mol.107.043182 ◽

2008 ◽

Vol 73 (6) ◽

pp. 1622-1631 ◽

Cited By ~ 17

Author(s):

Caroline Pinet ◽

Vincent Algalarrondo ◽

Sylvie Sablayrolles ◽

Bruno Le Grand ◽

Christophe Pignier ◽

...

Keyword(s):

Sodium Current ◽

Persistent Sodium Current ◽

Human Cardiomyocytes ◽

Protease Activated Receptor 1

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Y1767C, a Novel SCN5A Mutation Induces a Persistent Sodium Current and Potentiates Ranolazine Inhibition of NaV1.5 Channels

Biophysical Journal ◽

10.1016/j.bpj.2010.12.2494 ◽

2011 ◽

Vol 100 (3) ◽

pp. 421a

Author(s):

Hai Huang ◽

Silvia G. Priori ◽

Carlo Napolitano ◽

Michael E. O’Leary ◽

Mohamed Chahine

Keyword(s):

Sodium Current ◽

Persistent Sodium Current ◽

Scn5a Mutation

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A voltage-clamp analysis of currents underlying cyclic AMP-induced membrane modulation in isolated peptidergic neurons of Aplysia

Journal of Neurophysiology ◽

10.1152/jn.1984.52.2.340 ◽

1984 ◽

Vol 52 (2) ◽

pp. 340-349 ◽

Cited By ~ 69

Author(s):

L. K. Kaczmarek ◽

F. Strumwasser

Keyword(s):

Cell Culture ◽

Cyclic Amp ◽

Voltage Clamp ◽

Cultured Cells ◽

Sodium Current ◽

Negative Slope ◽

Spontaneous Discharge ◽

Inward Current ◽

Outward Currents ◽

Bag Cell Neurons

A variety of chemical and electrophysiological evidence indicates that the onset of afterdischarge and the subsequent profound enhancement of spike broadening that occur in the bag cell neurons of Aplysia are related to an increase in adenosine 3',5'-monophosphate-(cAMP) dependent protein phosphorylation. We have now used a two-electrode voltage clamp to study the properties of isolated bag cell neurons in cell culture and their response to 8 benzylthio-cAMP (8BTcAMP) and N6-n-butyl 8BTcAMP. These membrane-permeant and phosphodiesterase-resistant cAMP analogs induce spontaneous discharge and spike broadening in both the intact bag cell cluster and isolated bag cell neurons in cell culture. The dominant inward current in these cultured cells was found to be the calcium current, Ica, which was abolished by Co2+ (20 mM) or Ni2+ (10 mM) and could be observed in Na+-free media. In a minority of cells (2 of 12), in normal ionic media, a transient inward current was observed that was unaffected by Co2+ and Ni2+ and probably represents a sodium current. The three characterized potassium currents, the delayed rectifying current IK, the calcium-dependent current IC, and the early transient current IA, distinguished by their differing pharmacological and voltage-activation properties, were present in all healthy cells. Three effects of the cyclic AMP analogs (0.5 mM) on the electrical properties of these cells were 1) the emergence of a region of negative slope resistance in the steady-state I-V relations, 2) a depression of the net sustained outward currents due to depolarizing commands, and 3) a marked reduction in IA. When outward currents had been largely suppressed using high concentrations of tetraethylammonium (TEA) ions (100-460 mM) no effects of the cyclic AMP analogs could be observed on peak inward currents using NA+ and Ca2+ or Ba2+ as carriers of inward current. At least part of these electrical effects of the cyclic AMP analogs could be accounted for by a depression of a delayed potassium current and the A current.

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