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Klinische Neurophysiologie 2001; 32(3): 160-166
DOI: 10.1055/s-2001-17280
Originalia
© Georg Thieme Verlag Stuttgart · New York

Molekulare Mechanismen der Blockierung des muskulären nikotinischen Azetylcholinrezeptors

Molecular Block Mechanisms of the Muscular Nicotinic Acetylcholine ReceptorK.  Krampfl, J.  Bufler
  • Neurologische Klinik der Medizinischen Hochschule Hannover, Hannover
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Publication History

Publication Date:
19 September 2001 (online)

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Abstract

The development of the patch clamp technique made it possible to study the interaction between drugs or biological preparations and muscular nicotinic acetylcholine receptor channels (nAChR). By detailed quantitative analysis of the effects of various compounds on macroscopic sodium currents through nAChR we could identify two molecular mechanisms of block: open channel block and competitive block. In the first case the binding site of the blocker occurs exclusively at the receptor channel in the open state. The latter one is characterized by competitive binding to the binding site of the agonist. Using the same experimental approach on immunological diseases of neuromuscular transmission, we could show marked block of membrane currents when exposing the nAChR to IgG preparations from sera of myasthenia gravis patients.

Zusammenfassung

Die Patch-clamp-Technik erlaubt die detaillierte Analyse von Membranströmen durch muskuläre nikotinische Azetylcholinrezeptoren (nAChR). Diese sind eine wesentliche Zielstruktur der pharmakologischen Blockade der neuromuskulären Übertragung. Dabei kann man mit Hilfe der Patch-clamp-Technik zwei wesentliche molekulare Blockmechanismen unterscheiden: Offenkanalblock und kompetitiven Block. Beim Offenkanalblock ist die Bindungsstelle nur im offenen Zustand des Rezeptorkanals zugänglich, während beim kompetitiven Block die Blocksubstanz mit dem eigentlichen Agonisten um dieselbe Bindungsstelle konkurriert. Die Resultate quantitativer Analysen von Blockexperimenten können in reaktionskinetische Schemata integriert werden. Somit kann das Verhalten von nAChR in Anwesenheit verschiedener Blocksubstanzen per Computersimulation quantitativ vorausgesagt werden. Der Einsatz der Patch-clamp-Technik in der Untersuchung der Wirkung von IgG-Fraktionen von Myasthenia-gravis-Patienten auf nAChR konnte eine deutliche funktionelle Blockade der Rezeptoren nachweisen.

Key words

Nicotinic acetylcholine receptor - electrophysiology - pharmacology - myasthenia gravis

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PD Dr. J. Bufler

Neurologische Klinik · Medizinische Hochschule Hannover

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