Premium
Zinc inhibition of rat NR1/NR2A N ‐methyl‐ d ‐aspartate receptors
Author(s) -
Erreger Kevin,
Traynelis Stephen F.
Publication year - 2008
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.143941
Subject(s) - receptor , chemistry , zinc , nmda receptor , pharmacology , endocrinology , medicine , biochemistry , microbiology and biotechnology , biology , organic chemistry
Zinc ions (Zn 2+ ) are localized in presynaptic vesicles at glutamatergic synapses and released in an activity‐dependent manner. Modulation of NMDA‐type glutamate receptors by extracellular Zn 2+ may play an important role under physiological conditions and during pathologies such as ischaemia or seizure. Zn 2+ inhibits NMDA receptors containing the NR2A subunit with an IC 50 value in the low nanomolar concentration range. Here we investigate at the single‐channel level the mechanism of high affinity Zn 2+ inhibition of recombinant NR1/NR2A receptors expressed in HEK293 cells. Zn 2+ reversibly decreases the mean single‐channel open duration and channel open probability determined in excised outside‐out patches, but has no effect on single‐channel current amplitude. A parallel series of experiments demonstrates that lowering extracellular pH (increasing proton concentration) has a similar effect on NR1/NR2A single‐channel properties as Zn 2+ . Fitting the sequence of single‐channel events with kinetic models suggests that the association of Zn 2+ with its binding site enhances proton binding. Modelling further suggests that protonated channels are capable of opening but with a lower open probability than unprotonated channels. These data and analyses are consistent with Zn 2+ ‐mediated inhibition of NMDA receptors primarily reflecting enhancement of proton inhibition.