Влияние арахидоновой кислоты на хеморецептивные и биофизические свойства НМДА-каналов нейрональной мембраны

ВЫВОДЫ.

1. Методами пэтч-кламп регистрации ионных токов и быстрой аппликации веществ показано, что АА потенциирует ионные токи через НМДА-каналы. При этом, увеличение амплитуды пика превышает увеличение стационарного уровня тока примерно в 1,5 раза, свидетельствуя об усилении десенситизации каналов. Кинетическое моделирование привело к заключению, что АА (10 р, М) увеличивает как константу скорости открывания НМДА-каналов, так константу скорости входа в состояние десенситизации. Соответственно, вероятность открытого состояния НМДА-канала увеличивается примерно в 2,7 раза, а вероятность десенситизации — примерно в 1,3 раза.

2. Потенциация пикового тока возрастает с концентрацией АА (ЕС5о = 2,2 |лМ). Временной ход развития АА потенциации может быть описан моноэкспоненциальной функцией с постоянной времени топ, которая уменьшается от 17,2 до 2,1 сек с увеличением концентрации АА от 5 до 20 цМ. При отмывании клетки от АА восстановление тока происходит с постоянной времени г0№ ~ 30 сек, не зависящей от концентрации АА. Процессы потенциации/восстановления не зависят от частоты периодической стимуляции НМДА-каналов импульсами агониста, и, следовательно, от того, в каком состоянии, закрытом или открытом, находятся каналы. Кинетика потенциации/восстановления хорошо описывается в рамках бимолекулярной реакции.

3. Построена модель, описывающая встраивание АА в липид мембраны и воздействие на механо-рецептор НМДА-канала. Результаты моделирования показали, что модель хорошо описывает кинетику потенциации АА НМДА-токов только при низких концентрациях, А А (< 10 цМ).

4. Потенциация НМДА-токов АА не зависит от мембранного потенциала, концентраций агониста (аспартата) и коагониста (глицина) — не изменяется при действии на клетку блокатора протеин-киназы С кальфостина С, БН-агента дитиотрейтола, цинка или эозина. Таким образом, действие АА не опосредовано активацией протеин-киназы С или участками связывания агониста, коагониста, цинка, эозина, «редокс» -участка НМДА-рецептора.

5. Потенциация НМДА-токов АА зависит от величины внеклеточного рН: повышение рН с 6,5 до 7,0 увеличивает пик модифицированного тока, а дальнейшее подщелачивание среды уменьшает его так, что при рН 8.0 потенцирующий эффект АА полностью исчезает и сменяется обратным — ингибированием. АА изменяет потенциирующее действие полиамина спермина на НМДА-токи на блокирующее. Эти результаты свидетельствуют в пользу непосредственного взаимодействия АА с белковой молекулой НМДА-рецептора.

6. Ненасыщенные жирные кислоты (АА, олеиновая и у-линоленовая) потенциируют НМДА-токи, насыщенная пальмитиновая и функциональные производные АА (АА-Ев, АА-ЕА, АА-8Е, АА-ЭА) не оказывают на НМДА-токи существенного влияния, в то время как лизофосфолипид ЬРО блокирует их. Эти данные невозможно объяснить в рамках «конусной» теории, что свидетельствует о том, что потенциирующее влияние липофильных веществ на НМДА-токи зависит от наличия СООН-группы и ненасыщенности гидрофобного «хвоста» .

7. Увеличение НМДА-токов, вызываемое АА, не изменяется в присутствии блокаторов метаболического распада АА, индометацина и пара-бром-фенацила. Это свидетельствует о том, что АА действует на НМДА-рецепторы сама, а не продукты ее метаболического распада.

8. АА увеличивает видимую эффективность, 1С5о, блокаторов, препятствующих закрыванию канала (ТРегиА), и не влияет на эффективность «трэппинг-блокаторов» (Mg2+, ТРА и А-7), не взаимодействующих с воротной системой НМДА-канала.

9. Кинетическое моделирование блокады НМДА-каналов ТРА, Mg и А-7 в присутствии АА показало, что эти блокаторы устраняют вызванное АА увеличение вероятности открытого и десенситизированного состояний, т. е. демодифицируют НМДА-каналы.

БЛАГОДАРНОСТИ.

Автор благодарит профессора Бориса Израилевича Ходорова за чуткое руководство работой, А. И. Соболевского и Е. А. Вальдман как соавторов публикаций по материалам диссертации. Выражаю благодарность рук. лаборатории общей патологии нервной системы НИИ Общей патологии и патофизиологии Г. Н. Крыжановскому за большую помощь и постоянную поддержку. Я благодарна L.P. Wollmuth, В. В. Безуглову и Е. А. Вальдман за предоставленные вещества, С. Г. Кошелеву за техническую поддержку, а также И. Н. Шароновой и C.B. Ревенко за критическое обсуждение диссертации.

Работа поддержана Российским фондом фундаментальных исследований (гранты № 00−15−97 916, 99−04−48 770 и 01−04−6 018), а также грантом INTAS.

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