Several
polyamines have been shown to interact with a site on the
N-methyl-D-aspartate (
NMDA) receptor that regulates the binding of open channel blockers.
Spermine (SP) and
spermidine (SD),
polyamine agonists, enhanced binding of open channel blockers, whereas
arcaine (
ARC),
diethylenetriamine (
DET), and
putrescine (PUT),
polyamine antagonists, reduced the
polyamine enhancement of open channel blocker binding. We previously showed that SP had multiple actions on
NMDA receptor single-channel currents that underlie its effect on whole-cell
NMDA receptor current. At high concentrations, SP produced a voltage-dependent decrease in
NMDA receptor single-channel conductance and average open time. In the present study, another
polyamine agonist (SD) produced a similar reduction of
NMDA receptor single-channel conductance at higher concentrations. The
polyamine antagonists (
ARC,
DET, and PUT), however, produced a voltage-dependent reduction in
NMDA receptor whole-cell currents and reductions in single-channel conductance and average open time, even in the absence of
polyamine agonists. The rank order of potency for reduction of
NMDA receptor single-channel conductance by
polyamines was
ARC greater than SP greater than SD greater than PUT =
DET, a rank order similar to that for the inhibitory actions of
polyamines in receptor binding assays and for the effects of the antagonists on
NMDA receptor whole-cell currents. The
polyamine antagonist
DET did not block the reduction of single-channel conductance by the
polyamine agonist SP. In fact, the effects of SP and
DET on single-channel conductance were additive.
DET also showed a variable enhancement of
NMDA receptor whole-cell currents in some neurons, suggesting
polyamine agonist-like properties. These results are not consistent with the standard pharmacological profile for agonists and antagonists acting at the same site. Potential mechanisms for the effects of the
polyamines on single-channel conductance are discussed.