Down regulation of sodium channels in nerve terminals of spontaneously epileptic mice

Willow, Max; Taylor, Stephen M.; Catterall, William A.; Finnell, Richard H.

doi:10.1007/bf00711071

Cited by 31 publications

(49 citation statements)

References 17 publications

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“…Previous experiments have shown that local anesthetics and other sodium channel blocking drugs are indirect allosteric inhibitors of BTX binding and action (22)(23)(24)26), consistent with separate binding sites. Moreover, local anesthetics can block sodium channels activated by BTX without displacing the toxin, although higher concentrations are required than for unmodified sodium channels (27,28).…”

Section: Resultsmentioning

confidence: 70%

“…Binding of toxins at neurotoxin receptor site 2 is enhanced allosterically by the binding of ␣-scorpion toxins to neurotoxin receptor site 3 (10), brevetoxins to neurotoxin receptor site 5 (11,14), and pyrethroid insecticides binding at an additional receptor site (13,14,21). Toxin binding at site 2 is inhibited allosterically by binding of tetrodotoxin at neurotoxin receptor site 1 (15) and by local anesthetics and related anticonvulsant and antiarrhythmic drugs (22)(23)(24)(25)(26). Local anesthetic block of BTX-modified sodium channels requires higher concentrations of drug than block of unmodified channels but does not displace BTX from its receptor (18,27,28).…”

mentioning

confidence: 99%

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Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel

Linford

Cantrell

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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117

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The voltage-gated sodium channel is the site of action of more than six classes of neurotoxins and drugs that alter its function by interaction with distinct, allosterically coupled receptor sites. Batrachotoxin (BTX) is a steroidal alkaloid that binds to neurotoxin receptor site 2 and causes persistent activation. BTX binding is inhibited allosterically by local anesthetics. We have investigated the interaction of BTX with amino acid residues I1760, F1764, and Y1771, which form part of local anesthetic receptor site in transmembrane segment IVS6 of type IIA sodium channels. Alanine substitution for F1764 (mutant F1764A) reduces tritiated BTX-A-20-␣-benzoate binding affinity, causing a 60-fold increase in K d . Alanine substitution for I1760, which is adjacent to F1764 in the predicted IVS6 transmembrane alpha helix, causes only a 4-fold increase in K d . In contrast, mutant Y1771A shows no change in BTX binding affinity. For wildtype and mutant Y1771A, BTX shifted the voltage for halfmaximal activation Ϸ40 mV in the hyperpolarizing direction and increased the percentage of noninactivating sodium current to Ϸ60%. In contrast, these BTX effects were eliminated completely for the F1764A mutant and were reduced substantially for mutant I1760A. Our data suggest that the BTX receptor site shares overlapping but nonidentical molecular determinants with the local anesthetic receptor site in transmembrane segment IVS6 as well as having unique molecular determinants in transmembrane segment IS6, as demonstrated in previous work. Evidently, BTX conforms to a domain-interface allosteric model of ligand binding and action, as previously proposed for calcium agonist and antagonist drugs acting on L-type calcium channels.Voltage-gated sodium channels are responsible for the rapid depolarization during the initial phase of the action potential in most excitable cells (1). The brain sodium channel consists of a pore-forming ␣ subunit of Ϸ260 kDa associated with a 36-kDa ␤1 subunit and a 33-kDa ␤2 subunit (reviewed in ref.2). The primary structure of the ␣ subunit is organized in four homologous domains (I-IV) that contain six transmembrane segments (S1-S6) and an additional membrane-associated segment between S5 and S6 and are connected by large intracellular loops (3, 4).Potent neurotoxins specifically bind to more than six distinct but allosterically coupled receptor sites on the voltage-gated sodium channel and modify its function with lethal consequences (2, 5-7). The sodium channel is also the site of action for local anesthetics and certain anticonvulsant and antiarrhythmic drugs that are used therapeutically to decrease sodium channel activity in syndromes of hyperexcitability, such as cardiac arrhythmia and epileptic seizure (1,8,9). Although these sodium channel binding sites are distinct, allosteric interactions among the sites modulate drug and toxin binding (10-15). Neurotoxin receptor site 2 binds neurotoxins that cause persistent activation of sodium channels, including batrachotoxin (BTX), veratridine, ac...

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Section: Resultsmentioning

confidence: 70%

mentioning

confidence: 99%

Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel

Linford

Cantrell

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

117

124

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“…In addition to being intriguing candidate genes for neurological disorders based on their known function in neurotransmission, Na ? channel activity is known to be important in neurons in mouse models of spontaneous seizure disorders [34]. In 1998, a C121W substitution was reported [35] in a Na v 1 regulatory b1 subunit (SCN1B, chromosome 19q13) in a large GEFS ?…”

Section: Na V 1 and Gaba(a)rmentioning

confidence: 99%

The Genetics of Common Epilepsy Disorders: Lessons Learned from the Channelopathy Era

Subaran

Greenberg

2014

Curr Genet Med Rep

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Idiopathic epilepsies are thought to be almost entirely the result of genetic determinants, most of which remain undiscovered. It was once widely accepted that mutations that change the amino acid sequence of ion channel proteins were the major cause of these epilepsies, making epilepsy in general a ''channelopathy.'' Since then, more comprehensive analysis of ion channel-encoding genes has largely rejected this hypothesis for common forms of epilepsy. Here, we discuss some of the assumptions that led to the channelopathy hypothesis and propose ways to avoid similar mistakes going forward. We also offer insight into promising genetic candidates that we believe play a major role in susceptibility to common forms of idiopathic epilepsy.

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“…13,14) Furthermore, compounds that bind to neurotoxin receptor site 2 are thought to block Na + channels in a use-dependent manner. [15][16][17] The concept of use dependency can be further explained by the modulated receptor hypothesis, 18) which proposes that drug binding is tighter to open or inactivated channels than to resting states. These observations suggest that site 2 Na + channel blockers may have a minimal effect on normal neuronal signaling but may act more effectively during ischemic conditions, where the membrane potential is persistently depolarized.…”

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confidence: 99%

Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke

Seki

Takahashi

Aoyama

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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In investigating potent sodium (Na ) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na channels and a significantly low affinity for dopamine D 2 receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na channels, which suggests that 4b would act as a use-dependent Na channel blocker in sustained depolarization during ischemic stroke.Key words sodium channel blocker; ischemic stroke; neuroprotection; neurotoxin receptor site 2Despite their many efforts and the promising neuroprotective action of some drug candidates, such as N-methyl- and a persistent tendency for depolarization by blocking Na + channel inactivation and shifting activation to a more negative membrane potential. 13,14) Furthermore, compounds that bind to neurotoxin receptor site 2 are thought to block Na + channels in a use-dependent manner. [15][16][17] The concept of use dependency can be further explained by the modulated receptor hypothesis, 18) which proposes that drug binding is tighter to open or inactivated channels than to resting states. These observations suggest that site 2 Na + channel blockers may have a minimal effect on normal neuronal signaling but may act more effectively during ischemic conditions, where the membrane potential is persistently depolarized. In contrast, clinical trials of other neuroprotective agents, particularly NMDA receptor antagonists, have been discontinued because of their dose-limiting side effects. 19) Thus, Na + channel blockers are promising agents for the treatment of stroke because of their mechanism of action, and they have been in clinical development (Fig. 1). [20][21][22][23] In this paper, we report the synthesis, modification, and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as Na + channel blockers. ChemistryWe previously discovered compound 1, which had a potent binding affinity for the BTX binding site on Na + channels (Fig. 2), using high-throughput screening (HTS). However, this compound also showed a high affinity for dopamine D 2 receptors, which indicates a high clinical risk for extrapyramidal side effects. 24) Thus, we initiated a search for Na + channel blockers with high in vivo neuroprotective activity and a low affinity for dopamine D 2 receptors. SUN N8075 bearing a 1-phenoxy-3-piperazinyl-2-propanol moiety is a Na + channel blocker that lacks binding affinity to dopamine D 2 receptors. 23)Compound 1 has a 3-amino-1-(5-indanyloxy)-2-propanol moiRegular Article

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Down regulation of sodium channels in nerve terminals of spontaneously epileptic mice

Cited by 31 publications

References 17 publications

Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel

Interaction of batrachotoxin with the local anesthetic receptor site in transmembrane segment IVS6 of the voltage-gated sodium channel

The Genetics of Common Epilepsy Disorders: Lessons Learned from the Channelopathy Era

Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke

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