Nocistatin and Products of Its Proteolysis Are Dual Modulators of Type 3 Acid-Sensing Ion Channels (ASIC3) with Algesic and Analgesic Properties

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Dmitry I. Osmakov^1,2,a*, Nadezhda V. Tarasova^2,b, Andrey A. Nedorubov^3,c, Victor A. Palikov^4,d, Yulia A. Palikova^4,e, Igor A. Dyachenko^4,f, Yaroslav A. Andreev^1,2,g, and Sergey A. Kozlov^1,h

¹Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia

²Institute of Molecular Medicine, Sechenov First Moscow State Medical University, 119991 Moscow, Russia

³Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, 119991 Moscow, Russia

⁴Branch of the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 142290 Pushchino, Russia

^* To whom correspondence should be addressed.

Received September 15, 2023; Revised October 27, 2023; Accepted October 30, 2023

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The neuropeptide nocistatin (NS) is expressed by the nervous system cells and neutrophils as a part of a precursor protein and can undergo stepwise limited proteolysis. Previously, it was shown that rat NS (rNS) is able to activate acid-sensing ion channels (ASICs) and that this effect correlates with the acidic nature of NS. Here, we investigated changes in the properties of rNS in the course of its proteolytic degradation by comparing the effects of the full-size rNS and its two cleavage fragments on the rat isoform 3 ASICs (ASIC3) expressed in X. laevis oocytes and pain perception in mice. The rNS acted as both positive and negative modulator by lowering the steady-state desensitization of ASIC3 at pH 6.8-7.0 and reducing the channel’s response to stimuli at pH 6.0-6.9, respectively. The truncated rNSΔ21 peptide lacking 21 amino acid residues from the N-terminus retained the positive modulatory activity, while the C-terminal pentapeptide (rNSΔ30) acted only as a negative ASIC3 modulator. The effects of the studied peptides were confirmed in animal tests: rNS and rNSΔ21 induced a pain-related behavior, whereas rNSΔ30 showed the analgesic effect. Therefore, we have shown that the mode of rNS action changes during its stepwise degradation, from an algesic molecule through a pain enhancer to a pain reliever (rNSΔ30 pentapeptide), which can be considered as a promising drug candidate.

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KEY WORDS: neuropeptide, nocistatin, ASIC channels, electrophysiology, pain, analgesia

DOI: 10.1134/S0006297923120155

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