Possible mechanism of ligand-receptor binding of the synthetic tripeptide Ac-RRR-NH2 to the nociceptive neuron membrane
DOI:
https://doi.org/10.33910/2687-1270-2021-2-4-412-419Keywords:
arginine-containing tripeptide, NaV1.8 channels, nociceptive neuron, conformational analysis, patch-clamp methodAbstract
The article reports the discovery of a novel signaling cascade opioid-like receptor → Na,K-ATPase/Src → NaV1.8 channel in the nociceptive neuron membrane. Triggering this cascade results in the modulation of its effector unit—the NaV1.8 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 NaV1.8 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-NH2 to the NaV1.8 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 NaV1.8 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 NaV1.8 channel using the mechanism described earlier for a range of other short arginine-containing peptides. In view of the foregoing, the tripeptide Ac-RRR-NH2 is a promising analgesic.
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Copyright (c) 2022 Ilya V. Rogachevskii, Dmitriy M. Samosvat, Arina D. Kalinina, Georgy G. Zegrya, Boris V. Krylov, Svetlana A. Podzorova, Vera B. Plakhova
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