Nocistatin and products of its proteolysis as dual modulators of type 3 acid-sensing ion channels (ASIC3) with an algesic and analgesic effect

Мұқаба

Дәйексөз келтіру

Толық мәтін

Ашық рұқсат Ашық рұқсат
Рұқсат жабық Рұқсат берілді
Рұқсат жабық Тек жазылушылар үшін

Аннотация

The neuropeptide nocistatin (NS) is expressed by cells of the nervous system and neutrophils as part of a precursor protein and can undergo limited proteolysis through stepwise degradation. Previously, it was shown that rat NS (rNS) is able to activate acid-sensing ion channels (ASIC), but this effect correlated with the acidic nature of NS. In this work, we investigated the change in the properties of rNS during its degradation by a comparison of rNS and its two synthesized fragments. We estimated their activity on rat ASIC3 channels expressed in X. laevis oocytes, and the effects in pain tests on mice. We have shown that rNS combines the properties of both positive and negative modulators of ASIC3, which is expressed in the ability to lower the channel’s steady-state desensitization in the pH range 6.8-7.0 and the reduction of the channel’s response to stimuli in the 6.0-6.9 pH range. A shortened analogue (rNSΔ21) (21 amino acid residues (aa) from the N-terminus) retained the effect of the ASIC3 positive modulator only, while the C-terminal pentapeptide (rNSΔ30) retained the ability of the ASIC3 negative modulator only. This tendency was confirmed in animal tests, where rNS and rNSΔ21 induced pain related behavior, but rNSΔ30 showed an analgesic effect. Thus, we have shown the change of the rNS action mode during stepwise degradation, from an algesic molecule through a pain-enhancer to a pain-relief wherefore the final pentapeptide can even be considered as a promising starting point for further drug development.

Авторлар туралы

D. Osmakov

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences;Institute of Molecular Medicine, Sechenov First Moscow State Medical University

Email: osmadim@gmail.com
117997 Moscow, Russia;119991 Moscow, Russia

N. Tarasova

Institute of Molecular Medicine, Sechenov First Moscow State Medical University

119991 Moscow, Russia

A. Nedorubov

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

119991 Moscow, Russia

V. Palikov

Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

142290 Pushchino, Russia

Y. Palikova

Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

142290 Pushchino, Russia

I. Dyachenko

Branch of the Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

142290 Pushchino, Russia

Y. Andreev

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences;Institute of Molecular Medicine, Sechenov First Moscow State Medical University

117997 Moscow, Russia;119991 Moscow, Russia

S. Kozlov

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences

Email: serg@ibch.ru
117997 Moscow, Russia

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