Mechanism of action of galantamine on N-methyl-D-aspartate receptors in rat cortical neurons

Shigeki Moriguchi, William Marszalec, Xilong Zhao, Jay Z. Yeh, Toshio Narahashi

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Galantamine, a new Alzheimer's drug approved in the United States, is known to inhibit acetylcholinesterase and potentiate acetylcholine-induced currents in brain neurons. However, because both cholinergic and N-methyl-D-aspartate (NMDA) systems are down-regulated in the brain of Alzheimer's patients, we studied the effects of galantamine on NMDA receptors. NMDA-induced whole-cell currents were recorded from the rat multipolar cortical neurons in primary culture. NMDA currents recorded in Mg2+-free media without addition of glycine were reversibly potentiated by bath and U-tube applications of galantamine at 10 to 10,000 nM, showing a bell-shaped dose-response relationship. However, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate currents were not affected by galantamine. The maximum potentiation of NMDA currents to ∼130% of the control was obtained at 1 μM galantamine. The potentiation was due to a shift of the NMDA dose-response curve in the direction of lower NMDA concentrations. Glycine at 1 to 3000 nM enhanced NMDA currents, and potentiation by 1 μM galantamine and 1 to 300 nM glycine was additive. The glycine site antagonist 7-chlorokynurenic acid did not prevent the galantamine action. These results suggested that galantamine did not interact with the glycine binding site. Experiments with various concentrations of Mg2+ indicated that galantamine did not affect the Mg2+ blocking site of the NMDA receptor. PKC was involved in galantamine potentiation of NMDA currents, but protein kinase A, G i/Go proteins, and Gs proteins were not involved. Potentiation of the activity of NMDA receptors is deemed partially responsible for the improvement of cognition, learning, and memory in Alzheimer's patients.

Original languageEnglish
Pages (from-to)933-942
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume310
Issue number3
DOIs
Publication statusPublished - 2004 Sep
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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