Publication:
Probing temperature and capsaicin-induced activation of TRPV1 channel via computationally guided point mutations in its pore and TRP domains

Дата
2020
Авторы
Lubova, K. I.
Chugunov, A. O.
Volynsky, P. E.
Korolkova, Y. V.
Trofimov, Y. A.
Journal Title
Journal ISSN
Volume Title
Издатель
Научные группы
Организационные подразделения
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Организационная единица
Институт ядерной физики и технологий
Цель ИЯФиТ и стратегия развития - создание и развитие научно-образовательного центра мирового уровня в области ядерной физики и технологий, радиационного материаловедения, физики элементарных частиц, астрофизики и космофизики.
Выпуск журнала
Аннотация
© 2020 Elsevier B.V.In a recent computational study, we revealed some mechanistic aspects of TRPV1 (transient receptor potential channel 1) thermal activation and gating and proposed a set of probable functionally important residues — “hot spots” that have not been characterized experimentally yet. In this work, we analyzed TRPV1 point mutants G643A, I679A + A680G, and K688G/P combining molecular modeling, biochemistry, and electrophysiology. The substitution G643A reduced maximal conductivity that resulted in a normal response to moderate stimuli, but a relatively weak response to more intensive activation. I679A + A680G channel was severely toxic for oocytes most probably due to abnormally increased basal activity of the channel (“always open” gates). The replacement K688G presumably facilitated movements of TRP domain and disturbed its coupling to the pore, thus leading to spontaneous activation and enhanced desensitization of the channel. Finally, mutation K688P was suggested to impair TRP domain directed movement, and the mutated channel showed ~100-fold less sensitivity to the capsaicin, enhanced desensitization and weaker activation by the heat. Our results provide a better understanding of TRPV1 thermal and capsaicin-induced activation and gating. These observations provide a structural basis for understanding some aspects of TRPV1 channel functioning and depict potentially pathogenic mutations.
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Цитирование
Probing temperature and capsaicin-induced activation of TRPV1 channel via computationally guided point mutations in its pore and TRP domains / Lubova, K.I. [et al.] // International Journal of Biological Macromolecules. - 2020. - 158. - P. 1175-1183. - 10.1016/j.ijbiomac.2020.04.239
URI
https://www.doi.org/10.1016/j.ijbiomac.2020.04.239
 https://www.scopus.com/record/display.uri?eid=2-s2.0-85084829880&origin=resultslist
 http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=Alerting&SrcApp=Alerting&DestApp=WOS_CPL&DestLinkType=FullRecord&UT=WOS:000564490100001
 https://openrepository.mephi.ru/handle/123456789/21792
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