Molekulare Analyse von Blockierungsmechanismen AMPAerger Glutamatrezeptoren: Entwicklung neuer Therapiestrategien bei neurodegenerativen Erkrankungen

Zusammenfassung

Durch die Anwendung moderner elektrophysiologischer Verfahren, im Speziellen der „patch-clamp”-Technik in Kombination mit einem Verfahren des ultraschnellen Lösungswechsels an Membranflecken, das die experimentelle Untersuchung schneller postsynaptischer Prozesse erlaubt, wurden an rekombinanten AMPA-Typ-Glutamatrezeptoren in vitro pharmakologische Mechanismen auf molekularer Ebene untersucht. Wir konnten mit diesen Untersuchungen die Blockierungsmechanismen verschiedener Substanzklassen, Pyrazinen und Adamantanen, an verschiedenen rekombinanten AMPA-Typ-Glutamatrezeptoren am einzelnen Kanalprotein nachweisen. Es zeigte sich dass Pyrazinderivate einen reinen kompetitiven Block und Adamantane einen kombinierten Offenkanalblock und kompetitiven Block am Rezeptor verursachen. Durch die genaue Kenntnis und Analyse der molekularen Mechanismen der Rezeptorblockierung könnten zukünftig neue effektivere Therapiestrategien bei Prozessen der akuten oder chronischen Neurodegeneration entwickelt werden.

Abstract

By means of modern electrophysiological processes, in particular the „patch clamp” technique in combination with a process for the ultrarapid change of solvent at a membrane patch, which makes the experimental investigation of rapid, post-synaptic processes possible, the in vitro pharamcological mechanisms of recombinant AMPA-type glutamate receptors were examined at the molecular level. With these experiments we were able to detect the blocking mechanisms of various classes of compounds such as pyrazines and adamantanes at the various recombinant AMPA-type glutamate receptors on individual channel proteins. We found that pyrazine derivatives exert a purely competitive blockage at the receptors while adamantanes effect a combined open channel blockade and a competitive blockage at the receprtors. With the exact knowledge and analysis of the molecular mechanisms of receptor blocking it should be possible to develop new, effective therapeutic strategies against processes of acute or chronic neurodegeneration.

Key words

AMPA receptor - patchclamp - block mechanism

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