Molecular mechanism of modulation of nociceptive neuron membrane excitability by a tripeptide

Abstract

Using the whole-cell patch-clamp method, the ability of arginine-containing tripeptide Ac-RER-NH2, dipeptide Ac-RR-NH2, and free Arg molecule to modulate the membrane excitability of nociceptors was studied. Extracellular Ac-RER-NH2 upon interaction with the outer membrane of the nociceptive neuron decreases the Zeff value of the activation gating system of Nav1.8 channels. Thus, the tripeptide Ac-RER-NH2 can be considered as a new effective and safe analgesic.

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

“…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).…”

“…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.…”

“…The free arginine molecule (R) and the Ac-RR-NH 2 dipeptide have not been found to control voltage sensitivity of the Na V 1.8 channel activation gating device [ 7 ], which makes the RRR sequence the shortest potentially functional peptide sequence that includes only arginine residues. Therefore, an investigation of its effect on the Na V 1.8 channel is expected to provide evidence in support of the suggestion that only guanidinium groups of arginines are absolutely required for effective ligand-receptor binding of arginine-containing peptides.…”

Role of the Guanidinium Groups in Ligand–Receptor Binding of Arginine-Containing Short Peptides to the Slow Sodium Channel: Quantitative Approach to Drug Design of Peptide Analgesics

“…The modulating effects of arginine-containing short peptides on the Na V 1.8 channel in the primary sensory neuron have aroused our recent interest [1][2][3]. Slow sodium Na V 1.8 channels are responsible for nociceptive signal coding, and modulation of their functioning can evoke an antinociceptive effect on the organismal level [4,5].…”

“…Slow sodium Na V 1.8 channels are responsible for nociceptive signal coding, and modulation of their functioning can evoke an antinociceptive effect on the organismal level [4,5]. Several agents (Ac-RRR-NH 2 , H-RRR-OH, Ac-RERR-NH 2 ) have been shown to statistically significantly decrease the effective charge of the Na V 1.8 channel activation gating system at 100 nM, while the Ac-RER-NH 2 tripeptide was active at 1 µM [1][2][3]. On the other hand, free arginine molecules, the Ac-RR-NH 2 dipeptide, and the Ac-REAR-NH 2 tetrapeptide did not exhibit such an effect at 1 µM [1,2].…”