Arcaine blocks N-methyl-D-aspartate receptor responses by an open channel mechanism: Whole-cell and single-channel recording studies in cultured hippocampal neurons

S. D. Donevan, S. M. Jones, Michael A Rogawski

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Arcaine, a putative competitive antagonist at the polyamine site on the N-methyl-D-aspartate (NMDA) receptor complex, not only inhibits polyamine enhancement of NMDA-induced [3H]dizocilpine (MK-801) binding but also depresses binding in the absence of polyamines. In the present experiments, we investigated the mechanism of this latter effect in whole-cell and single-channel recordings from cultured rat hippocampal neurons. Arcaine produced a concentration-dependent block of NMDA-evoked inward currents (KD, 61 μM at -60 mV) but not those induced by kainate, α-amino-3-hydoxy-5-methyl-4-isoxazolepropionic acid, or γ-aminobutyric acid. The arcaine block was strongly voltage dependent and was almost completely relieved at positive holding potentials. Analysis of the voltage dependence indicated that the arcaine acceptor site appeared to sense 67% of the transmembrane electric field. In support of an open channel blocking mechanism, arcaine, like Mg2+, prevented dizocilpine from blocking the NMDA receptor channel. Moreover, increasing the dizocilpine concentration partially overcame the arcaine effect, indicating a competitive interaction between arcaine and dizocilpine. Spermine, which in our preparation usually produced only an arcaine-like voltage-dependent block of NMDA currents at high concentrations (>100 μM), had no effect on the block by arcaine at lower concentrations. In single-channel recordings, arcaine caused a concentration- and voltage-dependent decrease in apparent channel amplitude. Assuming a simple model of open channel block, we estimate the arcaine binding and unbinding rates as 4.4 × 108 M-1 sec-1 and 1.8 × 104 sec-1, respectively, which are comparable to the rates for open channel block by Zn2+ and substantially faster than those of Mg2+. These results indicate that arcaine inhibits NMDA-induced [3H]dizocilpine binding by blocking the open NMDA receptor channel, an action that is independent of the polyamine site.

Original languageEnglish (US)
Pages (from-to)727-735
Number of pages9
JournalMolecular Pharmacology
Issue number4
StatePublished - Apr 1992
Externally publishedYes


ASJC Scopus subject areas

  • Pharmacology

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