The up-regulation of voltage-gated sodium channels subtypes coincides with an increased sodium current in hippocampal neuronal culture model

Oxaliplatin is a chemotherapeutic drug widely used to treat various types of tumors. However, it can induce a serious peripheral neuropathy characterized by cold and mechanical allodynia that can even disrupt the treatment schedule. Since the approval of the agent, many laboratories, including ours, have focused their research on finding a drug or method to decrease this side effect. However, to date no drug that can effectively reduce the pain without causing any adverse events has been developed, and the mechanism of the action of oxaliplatin is not clearly understood. On the dorsal root ganglia (DRG) sensory neurons, oxaliplatin is reported to modify their functions, such as the propagation of the action potential and induction of neuropathic pain. Voltage-gated sodium channels in the DRG neurons are important, as they play a major role in the excitability of the cell by initiating the action potential. Thus, in this small review, eight studies that investigated the effect of oxaliplatin on sodium channels of peripheral neurons have been included. Its effects on the duration of the action potential, peak of the sodium current, voltage–response relationship, inactivation current, and sensitivity to tetrodotoxin (TTX) are discussed.

Download Full-text

Neurosteroids Allopregnanolone Sulfate and Pregnanolone Sulfate Have Diverse Effect on the α Subunit of the Neuronal Voltage-gated Sodium Channels Nav1.2, Nav1.6, Nav1.7, and Nav1.8 Expressed in Xenopus Oocytes

Anesthesiology ◽

10.1097/aln.0000000000000296 ◽

2014 ◽

Vol 121 (3) ◽

pp. 620-631 ◽

Cited By ~ 6

Author(s):

Takafumi Horishita ◽

Nobuyuki Yanagihara ◽

Susumu Ueno ◽

Yuka Sudo ◽

Yasuhito Uezono ◽

...

Keyword(s):

Sodium Channels ◽

Xenopus Oocytes ◽

Sodium Current ◽

Dependent Manner ◽

Sodium Currents ◽

Concentration Dependent Manner ◽

Α Subunit ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Α Subunits

Abstract Background: The neurosteroids allopregnanolone and pregnanolone are potent positive modulators of γ-aminobutyric acid type A receptors. Antinociceptive effects of allopregnanolone have attracted much attention because recent reports have indicated the potential of allopregnanolone as a therapeutic agent for refractory pain. However, the analgesic mechanisms of allopregnanolone are still unclear. Voltage-gated sodium channels (Nav) are thought to play important roles in inflammatory and neuropathic pain, but there have been few investigations on the effects of allopregnanolone on sodium channels. Methods: Using voltage-clamp techniques, the effects of allopregnanolone sulfate (APAS) and pregnanolone sulfate (PAS) on sodium current were examined in Xenopus oocytes expressing Nav1.2, Nav1.6, Nav1.7, and Nav1.8 α subunits. Results: APAS suppressed sodium currents of Nav1.2, Nav1.6, and Nav1.7 at a holding potential causing half-maximal current in a concentration-dependent manner, whereas it markedly enhanced sodium current of Nav1.8 at a holding potential causing maximal current. Half-maximal inhibitory concentration values for Nav1.2, Nav1.6, and Nav1.7 were 12 ± 4 (n = 6), 41 ± 2 (n = 7), and 131 ± 15 (n = 5) μmol/l (mean ± SEM), respectively. The effects of PAS were lower than those of APAS. From gating analysis, two compounds increased inactivation of all α subunits, while they showed different actions on activation of each α subunit. Moreover, two compounds showed a use-dependent block on Nav1.2, Nav1.6, and Nav1.7. Conclusion: APAS and PAS have diverse effects on sodium currents in oocytes expressing four α subunits. APAS inhibited the sodium currents of Nav1.2 most strongly.

Download Full-text

A Possible Explanation for a Neurotoxic Effect of the Anticancer Agent Oxaliplatin on Neuronal Voltage-Gated Sodium Channels

Journal of Neurophysiology ◽

10.1152/jn.2001.85.5.2293 ◽

2001 ◽

Vol 85 (5) ◽

pp. 2293-2297 ◽

Cited By ~ 221

Author(s):

Françoise Grolleau ◽

Laurence Gamelin ◽

Michèle Boisdron-Celle ◽

Bruno Lapied ◽

Marcel Pelhate ◽

...

Keyword(s):

Sodium Channels ◽

Calcium Ions ◽

Periplaneta Americana ◽

Sodium Current ◽

Current Amplitude ◽

Patch Clamp Technique ◽

Electrophysiological Properties ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Whole Cell Patch Clamp

Oxaliplatin, a new widely used anticancer drug, displays frequent, sometimes severe, acute sensory neurotoxicity accompanied by neuromuscular signs that look like the symptoms observed in tetany and myotonia. The whole cell patch-clamp technique was employed to investigate the oxaliplatin effects on the electrophysiological properties of short-term cultured dorsal unpaired median (DUM) neurons isolated from the CNS of the cockroach Periplaneta americana. Within the clinical concentration range, oxaliplatin (40–500 μM), applied intracellularly, decreased the amplitude of the voltage-gated sodium current resulting in a reduction of half the amplitude of the action potential. For comparison, two other platinum derivatives, cisplatin and carboplatin, were found to be ineffective at reducing the sodium current amplitude. In addition, we compared the oxaliplatin action to those of its metabolites dichloro-diaminocyclohexane platinum (dach-Cl2-platin) and oxalate. Oxalate (500 μM) was found to be effective, like oxaliplatin, at reducing the inward sodium current amplitude, whereas dach-Cl2-platin (500 μM) failed to change the current amplitude. Interestingly, the effect of oxalate or oxaliplatin could be mimicked by using intracellularly applied 10 mM bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA), known as chelator of calcium ions. We concluded that oxaliplatin was capable of altering the voltage-gated sodium channels through a pathway involving calcium ions probably immobilized by its metabolite oxalate. The medical interest of preventing acute neurotoxic side effects of oxaliplatin by infusing Ca2+ and Mg2+ is discussed.

Download Full-text

Postnatal Changes in the Inactivation Properties of Voltage-Gated Sodium Channels Contribute to the Mature Firing Pattern of Spinal Motoneurons

Journal of Neurophysiology ◽

10.1152/jn.00059.2008 ◽

2008 ◽

Vol 99 (6) ◽

pp. 2864-2876 ◽

Cited By ~ 6

Author(s):

K. P. Carlin ◽

J. Liu ◽

L. M. Jordan

Keyword(s):

Sodium Channels ◽

Firing Pattern ◽

Sodium Current ◽

Age Groups ◽

Force Production ◽

Postnatal Period ◽

Spinal Motoneurons ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Age Related

Most mammals are born with the necessary spinal circuitry to produce a locomotor-like pattern of neural activity. However, rodents seldom demonstrate weight-supported locomotor behavior until the second or third postnatal week, possibly due to the inability of the neuromuscular system to produce sufficient force during this early postnatal period. As spinal motoneurons mature they are seen to fire an increasing number of action potentials at an increasing rate, which is a necessary component of greater force production. The mechanisms responsible for this enhanced ability of motoneurons are not completely defined. In the present study we assessed the biophysical properties of the developing voltage-gated sodium current to determine their role in the maturing firing pattern. Using dissociated postnatal lumbar motoneurons in short-term culture (18–24 h) we demonstrate that currents recorded from the most mature postnatal age group (P10–P12) were significantly better able to maintain channels in an available state during repetitive stimulation than were the younger age groups (P1–P3, P4–P6, P7–P9). This ability correlated with the ability of channels to recover more quickly and more completely from an inactivated state. These age-related differences were seen in the absence of changes in the voltage dependence of channel gating. Differences in both closed-state inactivation and slow inactivation were also noted between the age groups. The results indicate that changes in the inactivation properties of voltage-gated sodium channels are important for the development of a mature firing pattern in spinal motoneurons.

Download Full-text