Метаботропные глутаматные рецепторы первой группы (mGluR1/5) и нейродегенеративные заболевания

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В обзоре описано участие метаботропных глутаматных рецепторов группы mGluR1/5 в механизмах нейродегенеративных заболеваний и опыт их использования в качестве терапевтической мишени на животных моделях. mGluR1/5 локализованы преимущественно на постсинаптической мембране нервной клетки, где они контактируют с двумя белками — Gαq/11 и Homer, посредством которых запускается несколько биохимических каскадов. Каскад белка Gαq/11 включает выброс Са2+ из эндоплазматического ретикулума (ER) через рецепторы к инозитол-1,4,5-трифосфату (IP3R) и активацию депо-управляемого входа Са2+. Каскад белка Gαq/11 включает также производство диацилглицерола с последующей активацией различных протеинкиназ и влиянием на геном. Белок Homer прямо контактирует с NMDA-рецепторами и опорными белками Shank, посредством которых он регулирует активность различных протеинкиназ, в том числе Akt и ERK1/2. Активация mGluR1/5 приводит к индукции длительной депрессии глутаматергической передачи, механизмом которой служит эндоцитоз AMPA-рецепторов, вызванный изменением уровня фосфорилирования белков и активацией генома.

Предполагается, что mGluR1/5 играют важную роль в патогенезе нейродегенеративных заболеваний. При болезни Альцгеймера mGluR1/5 выступают в качестве одной из мишеней для β-амилоидного пептида. Антагонисты mGluR1/5 вызывают нейропротекторный эффект на трансгенных мышах с болезнью Альцгеймера. Патогенез болезни Альцгеймера включает повышенный выброс Са2+ из ER благодаря патологической активности mGluR1/5, а также влиянию мутированного пресенилин-белка на Са2+ гомеостаз в ER. При этом восстановление уровня Са2+ в ER нарушено из-за влияния пресенилин-белка на депо-управляемый вход Са2+.

mGluR5 (но не mGluR1) рассматривают в качестве потенциальной терапевтической мишени для лечения болезни Паркинсона. Многочисленные работы, выполненные на моделях болезни Паркинсона на грызунах и приматах, выявили выраженный антипаркинсональный эффект при применении антагонистов mGluR5. Механизмы нейропротекторного действия антагонистов mGluR5 связывают с ограничением повышения внутриклеточного Са2+ благодаря снижению активации IP3- и NMDA-рецепторов. Болезнь Гентингтона связывают с мутацией гена HTT и способностью мутированного белка mhht сенситизировать IP3- и NMDA-рецепторы, вызывая тем самым перегрузку Са2+ в нейронах. Нейропротекторный эффект на трансгенных мышах с болезнью Гентингтона был получен при применении положительных аллостерических модуляторов mGluR5, которые способны избирательно включать каскад, связанный с белком Homer и вызывающий активацию Akt.

Об авторах

Елена Ивановна Солнцева

ФГБНУ «Научный центр неврологии»

Автор, ответственный за переписку.
Email: synaptology@mail.ru
Россия, Москва

Павел Денисович Рогозин

ФГБНУ «Научный центр неврологии»

Email: synaptology@mail.ru
Россия, Москва

Владимир Георгиевич Скребицкий

ФГБНУ «Научный центр неврологии»

Email: synaptology@mail.ru
Россия, Москва

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