A Possible Mechanism of Modulation of Slow Sodium Channels in the Sensory Neuron Membrane by Short Peptides

Rogachevsky, I. V.; Kalinina, A. D.; Penniyaynen, V. A.; Terekhin, S. G.; Подзорова, С. А.; Крылов, Б. В.; Plakhova, Vera B.

doi:10.1134/s0006350921040205

Cited by 4 publications

(7 citation statements)

References 26 publications

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“…This fact supports our suggestion that TP1 and TP2 bind directly to the Na V 1.8 channel due to intermolecular ion–ion bonding between positively charged guanidinium groups of the attacking peptide molecule and nucleophilic moieties of the Na V 1.8 channel. This suggestion has been put forward earlier when the effects of the Ac-RER-NH 2 tripeptide and the Ac-RERR-NH 2 tetrapeptide were investigated [ 7 , 8 ]. However, the aforementioned peptides contain glutamic acid residue (E).…”

Section: Discussionmentioning

confidence: 87%

“…Several arginine-containing short peptides have also been shown to modulate the Na V 1.8 channel activation gating device [ 7 , 8 ]. The peptides are suggested to bind directly to the Na V 1.8 channel due to intermolecular ion–ion bonding between positively charged guanidinium groups of the arginine side chains and nucleophilic moieties of the Na V 1.8 channel molecule.…”

Section: Introductionmentioning

confidence: 99%

“…The peptides are suggested to bind directly to the Na V 1.8 channel due to intermolecular ion–ion bonding between positively charged guanidinium groups of the arginine side chains and nucleophilic moieties of the Na V 1.8 channel molecule. Hence, it is a reasonable assumption that the distance between guanidinium groups should match certain criteria to provide electrostatic and steric complementarity for effective ligand-receptor binding [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Arginine-Containing Tripeptides as Analgesic Substances: The Possible Mechanism of Ligand-Receptor Binding to the Slow Sodium Channel

Rogachevskii

Plakhova

Penniyaynen

et al. 2022

IJMS

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Two short arginine-containing tripeptides, H-Arg-Arg-Arg-OH (TP1) and Ac-Arg-Arg-Arg-NH2 (TP2), have been shown by the patch-clamp method to modulate the NaV1.8 channels of DRG primary sensory neurons, which are responsible for the generation of nociceptive signals. Conformational analysis of the tripeptides indicates that the key role in the ligand-receptor binding of TP1 and TP2 to the NaV1.8 channel is played by two positively charged guanidinium groups of the arginine side chains located at the characteristic distance of ~9 Å from each other. The tripeptide effect on the NaV1.8 channel activation gating device has been retained when the N- and C-terminal groups of TP1 were structurally modified to TP2 to protect the attacking peptide from proteolytic cleavage by exopeptidases during its delivery to the molecular target, the NaV1.8 channel. As demonstrated by the organotypic tissue culture method, the agents do not affect the DRG neurite growth, which makes it possible to expect the absence of adverse side effects at the tissue level upon administration of TP1 and TP2. The data obtained indicate that both tripeptides can have great therapeutic potential as novel analgesic medicinal substances.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Arginine-Containing Tripeptides as Analgesic Substances: The Possible Mechanism of Ligand-Receptor Binding to the Slow Sodium Channel

Rogachevskii

Plakhova

Penniyaynen

et al. 2022

IJMS

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“…Используемый нами методологический подход был применен ранее для исследования способности ряда аргининсодержащих коротких пептидов модулировать активационное воротное устройство канала Na V 1.8 (Rogachevsky et al 2021). В цитируемой работе было высказано предположение, что для проявления пептидами этого физиологического эффекта расстояние между гуанидиновыми группами должно пре-И.…”

Section: результатыunclassified

Possible mechanism of ligand-receptor binding of the synthetic tripeptide Ac-RRR-NH2 to the nociceptive neuron membrane

Rogachevskii

Samosvat

Калинина

et al. 2022

Integrative Physiology

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The article reports the discovery of a novel signaling cascade opioid-like receptor → Na,K-ATPase/Src → Na V 1.8 channel in the nociceptive neuron membrane. Triggering this cascade results in the modulation of its effector unit-the Na V 1.8 channel activation gating device, whereas the Na,K-ATPase/Src complex performs the signal transducer function. The cascade has three targets. Their modulation by the attacking molecules may evoke an antinociceptive response at the peripheral level. The first target is the opioid-like receptor activated by a number of gamma-pyrone derivatives. The second target is the Na,K-ATPase/Src complex, with its transducer function controlled by ouabain at nanomolar (endogenous) concentrations. The third target is the Na V 1.8 channel activation gating device modulated by arginine-containing short peptides. The article discusses a possible mechanism of ligand-receptor binding of the arginine-containing tripeptide Ac-RRR-NH 2 to the Na V 1.8 channel in the primary sensory neuron membrane. Extracellular application of the tripeptide is shown by the patch-clamp method to decrease the voltage sensitivity of Na V 1.8 channels. Positively charged guanidinium groups of arginine side chains are supposed to play the key role in the ligand-receptor complex formation. The results of conformational analysis demonstrate that the distances between the guanidinium groups in the tripeptide molecule exceed 10 Å. The obtained data lead us to conclude that the studied tripeptide can bind to the Na V 1.8 channel using the mechanism described earlier for a range of other short arginine-containing peptides. In view of the foregoing, the tripeptide Ac-RRR-NH 2 is a promising analgesic.

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“…Previously, we have designed and investigated some arginine-containing short peptides (Ac-RRR-NH 2 , H-RRR-OH, Ac-RERR-NH 2 , Ac-PRARRA-NH 2 , Ac-PRERRA-NH 2 ) which significantly decrease the effective charge transferred by the Na V 1.8 channel activation gating system (Z eff ), being applied at 100 nM [ 7 , 8 , 9 ]. The observed decrease in this parameter due to the effects of the indicated peptides modulates the electrophysiological characteristics of the Na V 1.8 channel in such a way that the channel becomes unable to generate the high-frequency impulse firing in the nociceptive neuron membrane.…”

Section: Introductionmentioning

confidence: 99%

Analgesic Effect of the Lysine-Containing Short Peptide Is Due to Modulation of the NaV1.8 Channel Activation Gating System

Kalinina,

Rogachevskii,

Samosvat

et al. 2023

Life

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The present work continues our recent series of articles that aim to elucidate the ligand–receptor binding mechanism of short cationic peptides to the NaV1.8 channel in the nociceptive neuron. The applied methodological approach has involved several methods: the patch-clamp experimental evaluation of the effective charge of the NaV1.8 channel activation gating system, the organotypic tissue culture method, the formalin test, and theoretical conformational analysis. The lysine-containing short peptide Ac-KEKK-NH2 has been shown to effectively modulate the NaV1.8 channel activation gating system. As demonstrated by the organotypic tissue culture method, the studied short peptide does not trigger the downstream signaling cascades controlling neurite outgrowth and should not be expected to evoke adverse side effects. Conformational analysis of the Ac-KEKK-NH2 molecule has revealed that the distances between the positively charged amino groups of the lysine side chains are equal to 11–12 Å. According to the previously suggested mechanism of ligand–receptor binding of short peptides to the NaV1.8 channel molecule, Ac-KEKK-NH2 should exhibit an analgesic effect, which has been confirmed by the formalin test. The data obtained unequivocally indicate that the studied lysine-containing short peptide is a promising candidate for the role of a novel analgesic medicinal substance.

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A Possible Mechanism of Modulation of Slow Sodium Channels in the Sensory Neuron Membrane by Short Peptides

Cited by 4 publications

References 26 publications

Arginine-Containing Tripeptides as Analgesic Substances: The Possible Mechanism of Ligand-Receptor Binding to the Slow Sodium Channel

Arginine-Containing Tripeptides as Analgesic Substances: The Possible Mechanism of Ligand-Receptor Binding to the Slow Sodium Channel

Possible mechanism of ligand-receptor binding of the synthetic tripeptide Ac-RRR-NH2 to the nociceptive neuron membrane

Analgesic Effect of the Lysine-Containing Short Peptide Is Due to Modulation of the NaV1.8 Channel Activation Gating System

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