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The NMDA receptor opens in response to binding of NMDA and glycine. However, it remains unclear where and how gating of the NMDA receptor pore is accomplished. We show that different point mutations between S645 and I655 (thus including the highly conserved SYTANLAAF motif) of M3c in NR2B lead to constitutively open channels. The current through these(More)
The antiepileptic effect of felbamate (FBM) is ascribable to gating modification of NMDA receptors. Using site-directed mutagenesis and electrophysiological studies, we found that single-point mutations of four pairs of homologous residues in the external vestibule of the receptor pore, namely V644(NR1)-L643(NR2B) (the two inner pairs) and(More)
BACKGROUND Despite the structural differences, local anesthetics, anticonvulsants, and tricyclic antidepressants exert similar use-dependent actions against voltage-gated Na channels, which may be contributory to pain control. The authors explore whether these drugs could doubly occupy the channel and exert synergic clinical effect. METHODS The authors(More)
The fourth segment of domain 4 (S4/D4) in Na+ channels is a voltage sensor especially implicated in channel inactivation. Although there has been evidence that S4/D4 moves externally during membrane depolarization, whether (and if so, how) the movement leads to conformational changes of the inactivation gate remains unknown. We added a positive charge just(More)
Parkinson’s disease (PD) is one of the most prevalent movement disorder caused by degeneration of the dopaminergic neurons in substantia nigra pars compacta. Deep brain stimulation (DBS) at the subthalamic nucleus (STN) has been a new and effective treatment of PD. It is interesting how a neurological disorder caused by the deficiency of a specific chemical(More)
The anticonvulsant effect of felbamate (FBM) is ascribable to inhibition of N-methyl-d-aspartate (NMDA) currents. Using electrophysiological studies in rat hippocampal neurons to examine the kinetics of FBM binding to and unbinding from the NMDA channel, we show that FBM modifies NMDA channel gating via a one-to-one binding stoichiometry and has(More)
Tetrodotoxin-resistant (TTX-R) Na(+) channels are much less susceptible to external TTX but more susceptible to external Cd(2+) block than tetrodotoxin-sensitive (TTX-S) Na(+) channels. Both TTX and Cd(2+) seem to block the channel near the "DEKA" ring, which is probably part of a multi-ion single-file region adjacent to the external pore mouth and is(More)
The N-methyl-d-aspartate receptor (NMDAR) channel is one of the major excitatory amino acid receptors in the mammalian brain. Since external Mg(2+) blocks the channel in an apparently voltage-dependent fashion, this ligand-gated channel displays intriguing voltage-dependent control of Na(+) and Ca(2+) permeability and thus plays an important role in(More)
Tetrodotoxin-resistant (TTX-R) Na(+) channels are 1,000-fold less sensitive to TTX than TTX-sensitive (TTX-S) Na(+) channels. On the other hand, TTX-R channels are much more susceptible to external Cd(2+) block than TTX-S channels. A cysteine (or serine) residue situated just next to the aspartate residue of the presumable selectivity filter "DEKA" ring of(More)
OBJECTIVE We have reported that intrinsic membrane properties, especially T-type Ca2+ channels, play a key role in the genesis of burst discharges in the subthalamic nucleus (STN) and parkinsonian locomotor symptoms. Whether deep brain stimulation (DBS) exerts its clinical benefits on Parkinson disease (PD) with changes in T currents or other conductances,(More)