Ion Channels of Excitable Membranes

Ovchinnikov, Yu.A.

doi:10.1007/978-94-009-7755-6_30

Cited by 10 publications

(10 citation statements)

References 10 publications

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“…Equilibration rates are a function of on-rate and concentration as well as off-rates according to K obs = k on *[CPD] + k off . 3 A faster k on and/or k off , therefore, increases equilibration rates. By comparing the equilibration rates at concentrations 3fold higher relative to the IC 50 , which are similar to the EC 50 brain concentrations found to suppress seizures in MES rodent models, 4,50 we found that these XPC compounds had a much slower equilibration rate than CBZ and PHY (Figure 3C).…”

Section: ■ Discussionmentioning

confidence: 99%

“…k on and k off are proportional to the transitional state energy barriers encountered by a ligand when engaging or dissociating from the binding site and, therefore, give information about what is driving potency; the rate of binding or unbinding or a combination of both. 3 We measured the kinetics of binding to Na V 1.6 channels using a protocol that tracks the inhibition over 100 s of holding at the V 0.5 (Figure 3A). The potencies for the compounds are measured at the end of 100 s at the V 0.5 (Figure 3B).…”

Section: Xpc-7224 and Xpc-5462 Are Molecularly Selectivementioning

confidence: 99%

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Molecular Pharmacology of Selective Na_V1.6 and Dual Na_V1.6/Na_V1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo

Goodchild,

Shuart,

Williams

et al. 2024

ACS Chem. Neurosci.

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Voltage-gated sodium channel (Na V ) inhibitors are used to treat neurological disorders of hyperexcitability such as epilepsy. These drugs act by attenuating neuronal action potential firing to reduce excitability in the brain. However, all currently available Na V -targeting antiseizure medications nonselectively inhibit the brain channels Na V 1.1, Na V 1.2, and Na V 1.6, which potentially limits the efficacy and therapeutic safety margins of these drugs. Here, we report on XPC-7724 and XPC-5462, which represent a new class of small molecule Na V -targeting compounds. These compounds specifically target inhibition of the Na V 1.6 and Na V 1.2 channels, which are abundantly expressed in excitatory pyramidal neurons. They have a > 100-fold molecular selectivity against Na V 1.1 channels, which are predominantly expressed in inhibitory neurons. Sparing Na V 1.1 preserves the inhibitory activity in the brain. These compounds bind to and stabilize the inactivated state of the channels thereby reducing the activity of excitatory neurons. They have higher potency, with longer residency times and slower off-rates, than the clinically used antiseizure medications carbamazepine and phenytoin. The neuronal selectivity of these compounds is demonstrated in brain slices by inhibition of firing in cortical excitatory pyramidal neurons, without impacting fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform activity in an ex vivo brain slice seizure model, whereas XPC-7224 does not, suggesting a possible requirement of Nav1.2 inhibition in 0-Mg 2+ -or 4-AP-induced brain slice seizure models. The profiles of these compounds will facilitate pharmacological dissection of the physiological roles of Na V 1.2 and Na V 1.6 in neurons and help define the role of specific channels in disease states. This unique selectivity profile provides a new approach to potentially treat disorders of neuronal hyperexcitability by selectively downregulating excitatory circuits.

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Section: ■ Discussionmentioning

confidence: 99%

Section: Xpc-7224 and Xpc-5462 Are Molecularly Selectivementioning

confidence: 99%

Molecular Pharmacology of Selective Na_V1.6 and Dual Na_V1.6/Na_V1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo

Goodchild,

Shuart,

Williams

et al. 2024

ACS Chem. Neurosci.

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“…In all studied conditions (polar and neutral membrane, 250/50 and 50/250 mM KCl gradients), the sign obtained of the measured currents without applied voltage is consistent with pores displaying cationic selectivity. However, the widely accepted magnitude to quantify selectivity is the so-called reversal potential (RP) 64 , which is the voltage required to yield zero current under a transmembrane gradient (the horizontal intercept of the I-V curve). Once the measured RP is introduced into the Goldman-Hodgkin-Katz (GHK) equation, we can obtain the permeability ratio P+ /P- 65 .…”

Section: Tse5-ct Forms Ion-selective Membrane Pores In Vitromentioning

confidence: 99%

The P. aeruginosa Type VI Secretion System Effector Tse5 Forms Ion-Selective Membrane Pores that Disrupt the Membrane Potential of Intoxicated Cells

González-Magaña

Altuna

Queralt-Martín

et al. 2021

Preprint

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The Type VI Secretion System (T6SS) of Pseudomonas aeruginosa injects effector proteins into neighbouring competitors and host cells, providing a fitness advantage that allows this opportunistic nosocomial pathogen to persist and prevail during the onset of infections. However, despite the high clinical relevance of P. aeruginosa, the identity and mode of action of most P. aeruginosa T6SS-dependent effectors remain to be discovered. Here, we report the molecular mechanism of Tse5-CT, which is the toxic auto-proteolytic product of the P. aeruginosa T6SS exported effector Tse5. Our results demonstrate Tse5-CT is a pore-forming toxin that can transport ions across the membrane, causing membrane depolarisation and bacterial death. The membrane potential regulates a wide range of essential cellular functions, and therefore membrane depolarisation is an efficient strategy to compete with other microorganisms in polymicrobial environments.

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“…Ion channels are transmembrane proteins that regulate ion flux across cell membranes and play a key role in controlling the electrical properties and excitability of neurons (Hille, 2001). In the 1990s, the discovery of the first disease‐causing monogenetic mutations in ion channels led to the identification of a new group of diseases, known as channelopathies.…”

Section: Neurodevelopmental Disorders With Epilepsy and Epileptic Enc...mentioning

confidence: 99%

Recent advances in gene therapy for neurodevelopmental disorders with epilepsy

Turner

Zourray

Schorge³

et al. 2020

Journal of Neurochemistry

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Ion Channels of Excitable Membranes

Cited by 10 publications

References 10 publications

Molecular Pharmacology of Selective Na_V1.6 and Dual Na_V1.6/Na_V1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo

Molecular Pharmacology of Selective Na_V1.6 and Dual Na_V1.6/Na_V1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo

The P. aeruginosa Type VI Secretion System Effector Tse5 Forms Ion-Selective Membrane Pores that Disrupt the Membrane Potential of Intoxicated Cells

Recent advances in gene therapy for neurodevelopmental disorders with epilepsy

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Ion Channels of Excitable Membranes

Cited by 10 publications

References 10 publications

Molecular Pharmacology of Selective NaV1.6 and Dual NaV1.6/NaV1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo

Molecular Pharmacology of Selective NaV1.6 and Dual NaV1.6/NaV1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo

The P. aeruginosa Type VI Secretion System Effector Tse5 Forms Ion-Selective Membrane Pores that Disrupt the Membrane Potential of Intoxicated Cells

Recent advances in gene therapy for neurodevelopmental disorders with epilepsy

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Molecular Pharmacology of Selective Na_V1.6 and Dual Na_V1.6/Na_V1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo

Molecular Pharmacology of Selective Na_V1.6 and Dual Na_V1.6/Na_V1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo