Ketamine Blockade of Voltage-gated Sodium Channels

Background The general anesthetic ketamine is known to be an N-methyl-D-aspartate receptor blocker. Although ketamine also blocks voltage-gated sodium channels in a local anesthetic-like fashion, little information exists on the molecular pharmacology of this interaction. We measured the effects of ketamine on sodium channels. Methods Wild-type and mutant (F1579A) recombinant rat skeletal muscle sodium channels were expressed in Xenopus oocytes. The F1579A amino acid substitution site is part of the intrapore local anesthetic receptor. The effect of ketamine was measured in oocytes expressing wild-type or mutant sodium channels using two-electrode voltage clamp. Results Ketamine blocked sodium channels in a local anesthetic-like fashion, exhibiting tonic blockade (concentration for half-maximal inhibition [IC50] = 0.8 mm), phasic blockade (IC50 = 2.3 mm), and leftward shift of the steady-state inactivation; the parameters of these actions were strongly modified by alteration of the intrapore local anesthetic binding site (IC50 = 2.1 mm and IC50 = 10.3 mm for tonic and phasic blockade, respectively). Compared with lidocaine, ketamine showed greater tonic inhibition but less phasic blockade. Conclusions Ketamine interacts with sodium channels in a local anesthetic-like fashion, including sharing a binding site with commonly used clinical local anesthetics.

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Inhibition of Nav1.7 and Nav1.4 Sodium Channels by Trifluoperazine Involves the Local Anesthetic Receptor

Journal of Neurophysiology ◽

10.1152/jn.00354.2006 ◽

2006 ◽

Vol 96 (4) ◽

pp. 1848-1859 ◽

Cited By ~ 13

Author(s):

Patrick L. Sheets ◽

Peter Gerner ◽

Chi-Fei Wang ◽

Sho-Ya Wang ◽

Ging Kuo Wang ◽

...

Keyword(s):

Sodium Channels ◽

Local Anesthetic ◽

Receptor Site ◽

Inhibitory Peptide ◽

Sensory Blockade ◽

Voltage Gated Sodium Channels ◽

State Dependent ◽

Steady State Inactivation ◽

Channel Interactions

The calmodulin (CaM) inhibitor trifluoperazine (TFP) can produce analgesia when given intrathecally to rats; however, the mechanism is not known. We asked whether TFP could modulate the Nav1.7 sodium channel, which is highly expressed in the peripheral nervous system and plays an important role in nociception. We show that 500 nM and 2 μM TFP induce major decreases in Nav1.7 and Nav1.4 current amplitudes and that 2 μM TFP causes hyperpolarizing shifts in the steady-state inactivation of Nav1.7 and Nav1.4. CaM can bind to the C-termini of voltage-gated sodium channels and modulate their functional properties; therefore we investigated if TFP modulation of sodium channels was due to CaM inhibition. However, the TFP inhibition was not replicated by whole cell dialysis of a calmodulin inhibitory peptide, indicating that major effects of TFP do not involve a disruption of CaM-channel interactions. Rather, our data show that TFP inhibition is state dependent and that the majority of the TFP inhibition depends on specific amino-acid residues in the local anesthetic receptor site in sodium channels. TFP was also effective in vivo in causing motor and sensory blockade after subfascial injection to the rat sciatic nerve. The state-dependent block of Nav1.7 channels with nanomolar concentrations of TFP raises the possibility that TFP, or TFP analogues, might be useful for regional anesthesia and pain management and could be more potent than traditional local anesthetics.

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Purification and Characterization of JZTx-14, a Potent Antagonist of Mammalian and Prokaryotic Voltage-Gated Sodium Channels

Toxins ◽

10.3390/toxins10100408 ◽

2018 ◽

Vol 10 (10) ◽

pp. 408 ◽

Cited By ~ 1

Author(s):

Jie Zhang ◽

Dongfang Tang ◽

Shuangyu Liu ◽

Haoliang Hu ◽

Songping Liang ◽

...

Keyword(s):

Sodium Channels ◽

Resting State ◽

Purification And Characterization ◽

Voltage Gated ◽

Voltage Gated Sodium Channels ◽

Steady State Inactivation ◽

Ic50 Values ◽

Gating Modifier ◽

Potent Antagonist

Exploring the interaction of ligands with voltage-gated sodium channels (NaVs) has advanced our understanding of their pharmacology. Herein, we report the purification and characterization of a novel non-selective mammalian and bacterial NaVs toxin, JZTx-14, from the venom of the spider Chilobrachys jingzhao. This toxin potently inhibited the peak currents of mammalian NaV1.2–1.8 channels and the bacterial NaChBac channel with low IC50 values (<1 µM), and it mainly inhibited the fast inactivation of the NaV1.9 channel. Analysis of NaV1.5/NaV1.9 chimeric channel showed that the NaV1.5 domain II S3–4 loop is involved in toxin association. Kinetics data obtained from studying toxin–NaV1.2 channel interaction showed that JZTx-14 was a gating modifier that possibly trapped the channel in resting state; however, it differed from site 4 toxin HNTx-III by irreversibly blocking NaV currents and showing state-independent binding with the channel. JZTx-14 might stably bind to a conserved toxin pocket deep within the NaV1.2–1.8 domain II voltage sensor regardless of channel conformation change, and its effect on NaVs requires the toxin to trap the S3–4 loop in its resting state. For the NaChBac channel, JZTx-14 positively shifted its conductance-voltage (G–V) and steady-state inactivation relationships. An alanine scan analysis of the NaChBac S3–4 loop revealed that the 108th phenylalanine (F108) was the key residue determining the JZTx-14–NaChBac interaction. In summary, this study provided JZTx-14 with potent but promiscuous inhibitory activity on both the ancestor bacterial NaVs and the highly evolved descendant mammalian NaVs, and it is a useful probe to understand the pharmacology of NaVs.

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