Нейротоксины - инструменты исследования мембран нервной системы тема автореферата и диссертации по химии, 02.00.10 ВАК РФ

ВВЕДЕНИЕ.

ГЛАВА Г. ХИМИЧЕСКИЕ И БИОЛОГИЧЕСКИЕ СВОЙСТВА НЕЙРОТОКСИ

НОВ АКСОЭДЛЬНОГО ДЕЙСТВШ (Литературный обзор).

I.I. Нейротоксины яда скорпионов

1,2* Полипептидные нейротоксины морских анемон

1.3. Механизм действия и рецепция токсинов скорпионов и анемон.

1.4. Токсины скорпиона - блокаторы калиевых каналов . . . . .3d

1.5. Токсичные полипептидда немертин

1*6. Алкалоидные нейротоксины

1.7. Механизм действия и рецепция алкалоидных нейротоксинов

I.8- Токсины, вызывающие деполяризацию аксональной мембраны.

1.9. Тетродотоксин и сакситоксин - блокаторы натриевых каналов.

1.10. Механизм действия и рецепция токсинов-блока-торов.

1.11. Другие природные нейротоксины аксонального действия.

РЕЗУЛЬТАТЫ И ИХ ОБСУЖДЕНИЕ.

ГЛАВА П. ВЫДЕЛЕНИЕ И ХАРАКТЕРИСТИКА ПОЛИПЕПТИДНЫХ ТОКСИНОВ

ГЛАВА Ш. СТРУКТУРА ПОЛИПЕПТИДНЫХ ТОКСИНОВ.

ГЛАВА 1У.ВЗАИМ0ДЕЙСТВИЕ НЕЙРОТОКСИНОВ С МЕМБРАНОЙ НЕРВНОЙ КЛЕТКИ.

ГЛАВА У- ВЫДЕЛЕНИЕ И ХАРАКТЕРИСТИКА КОМПОНЕНТОВ НАТРИЕВОГО КАНАЛА.

ШВА У1. ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ.

У1Л. Материалы.

У1.2. Выделение и характеристика полипептидных токсинов

УГ.З. Структурный анализ полипептидных токсинов . . 175 У1.4. Изучение взаимодействия аксональных нейротоксинов с электровозбудимыми мембранами . . 187 У1.5. Выделение и характеристика компонентов натриевого канала.

ВЫВОДЫ.

В современной науке центральное место принадлежит выяснению молекулярных: основ функционирования нервной системы человека и животных и прежде всего расшифровке механизмов генерации и передачи нервного возбуждения. Особый интерес связан с исследованием ионных каналов мембраны нервной клетки, поскольку именно они играют определяющую роль в процессах проведения нервного импульса. Сходные в функциональном плане ионные каналы обусловливают сокращение мышщ. Проблема изучения общих принципов функционирования мембран нервного волокна еще недавно являлась предметом чисто фундаментальных исследований. В настоящее время ясен ее важнейший практический аспект - управление функцией нервной клетки и поиск принципиально новых лекарственных препаратов для лечения расстройств нервной системы.

В настоящее время достаточно подробно изучена функциональная организация нервной системы и выяснена определяющая роль клеточных мембран в проявлении многих ее функций. Различные ре-цепторные центры нервных клеток обычно имеют мембранную природу. Генерация нервного возбуждения осуществляется благодаря работе специализированных мембранных транспортных структур - ионных каналов. Многие функционально важные мембранные компоненты хорошо охарактеризованы электрофизиологическими методами, однако, их дальнейшее исследование невозможно без идентификации и выделения соответствующих клеточных элементов в индивидуальном виде» При этом надежная идентификация имеет важнейшее значение, так как ионные каналы и нейрорецепторы часто обладают функциональной активностью только при наличии "нативного" мембранного окружения, а практически все методы их выделения связаны с разрушением мембранной структуры различными детергентами.

Известно, что многие функционально важные системы нервной клетки являются мишенью действия природных нейротоксинов. Так, существуют целые семейства нейротоксинов, способных селективно воздействовать на пресинаптическую мембрану нервных окончаний или ионные каналы аксонального волокна» Есть все основания полагать г что эти токсины можно использовать в качестве своеобразных молекулярных инструментов исследования разнообразных компонентов нервных мембран* Такой подход продемонстрирован в настоящей работе на примере изучения молекулярной организации быстрых натриевых-каналов, ответственных за генерацию ж проведение нервного импульса.

Использование нейротоксинов в качестве инструментов исследования мембран нервной системы предусматривает прежде всего поиск новых токсинов, а также выяснение механизма действия и структурных особенностей этих уникальных природных биорегуляторов» Подобные задача имеют важное самостоятельное значение , поскольку способствуют разработке перспективных фармакологических средств и созданию на их основе принципиально новых лекарственных препаратов.

Многие природные нейротоксины несомненно могут успешно применяться для идентификации и дальнейшего исследования разнообразных структур мембраны нервной клетки. Такое использование нейротоксинов требует решения целого ряда проблем по их структурно-функциональному анализу, получению модифицированных производных и, естественно, разработке методов выделения из природных ядов^ В связи с этим представлялось важным осуществить комплексное изучение различных токсинов и разработать общие подходы для их выделения, характеристики и использования в качестве инструментов исследования наиболее значимых функциональных систем мембраны нервной клетки.

Постановка такой проблемы учитывает необходимость целенаправленного изучения как самих токсических компонентов яда разнообразных- животныхг так и возможности их применения как уникальных биорегуляторов, влияющих на функционирование живой клетки- Представлялось целесообразным выбрать в качестве непосредственного объекта исследования быстрые натриевые каналы - важнейшие представители семейства* электроуправляемых ионных каналовг непосредственно обусловливающих феномен возбудимости мембран нервной системы»

Таким образом, основной целью настоящего исследования явилась разработка общих принципов использования нейротоксинов для исследования функциональных систем мембран нервной клетки.

Для выполнения поставленной цели решались следующие основные задачи, несомненно имеющие важное самостоятельное значение:

- разработка методов выделения индивидуальных полипептид-ныхт токсинов, продуцируемых: различными ядовитыми животными;

- структурный анализ выделенных полипептидных токсинов и определение особенности их строения;

- получение разнообразных модифицированных производных нейротоксинов и исследование их взаимодействия с мембранами нервных клеток;

- идентификация, выделение и характеристика компонентов быстрого* натриевого канала мембран мозга крыс.

Автор выражает глубокую признательность академику Ю.А.Овчинникову за постоянное внимание к данной работе.

ВЫВОДЫ

I. Проведено комплексное исследование нейротоксинов, взаимодействующих с электровозбудимыми мембранами, на основе которого разработаны общие принципы использования этих природных биорегуляторов для изучения функционально важных систем нервной клетки.

2- Впервые осуществлено систематическое исследование всех основных групп нейротоксинов, взаимодействующих с мембраной' нервной: клетки. Предложены общие методы выделения полипептидных токсинов из яда различных животных. При помощи этих методов получено в индивидуальном виде и охарактеризовано 34: токсина, из которых 25: выделено впервые. Открыто существование нового типа инсектотоксинов яда скорпиона. Выделенные полипептидные токсины обладают аксональным, пресинаптическим, постсинаптическим и цитотоксическим действием, что позволяет их использовать для идентификации и изучения соответствующих мембранных рецепторных систем.

3. Определена структура 12 полипептидных токсинов. Установлены основные принципы строения нового типа инсектотоксинов яда скорпиона. Исследованы структурные закономерностиг характерные для нейротоксинов из яда среднеазиатских скорпионов, взаимодействующих: с быстрыми натриевыми каналами электровозбудимых мембран.

4. Разработаны методы получения модифицированных полипептидных- токсинов, сохраняющих биологическую активность. Получены аналоги нейротоксинов с высоким уровнем молярной радиоактивности, которые можно использовать для надежной идентификации натриевых каналов нервной клетки» Изучено взаимодействие ряда нейротоксинов с препаратами электровозбудимых мембран. Установлено, что у-токсин скорпиона и тетродотоксин являются наиболее эффективными инструментами исследования натриевого канала.

Впервые выделены и охарактеризованы все индивидуальные компоненты натриевого канала электровозбудимых мембран млекопитающих. Показано, что основные функциональные компоненты канала представляют собой эквимолярный комплекс гликопротеинов молекулярной массы 260, 39 и 37 кДа. Предложен препаративный метод получения индивидуальных субвединиц натриевого канала из мозга крысы; установлены их аминокислотные и углеводные составы, обнаружено отсутствие у них свободных Я-концевых аминокислотных остатков. Изучена аминокислотная последовательность ряда трип-тических пептидов Л-субъединицы канала. На основании полученной информации синтезирован нуклеотидный зонд и начаты эксперименты по идентификации структурного гена натриевого канала мозга крысы.

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