PMID- 36305341
OWN - NLM
STAT- MEDLINE
DCOM- 20221220
LR  - 20231202
IS  - 1530-0277 (Electronic)
IS  - 0145-6008 (Print)
IS  - 0145-6008 (Linking)
VI  - 46
IP  - 12
DP  - 2022 Dec
TI  - Effects of ethanol on GluN1/GluN2A and GluN1/GluN2B NMDA receptor-ion channel 
      gating kinetics.
PG  - 2203-2213
LID - 10.1111/acer.14965 [doi]
AB  - BACKGROUND: The N-methyl-D-aspartate receptor (NMDAR) is a major molecular target 
      of alcohol action in the central nervous system, yet many aspects of alcohol's 
      modulation of the activity of this ion channel remain unclear. We and others have 
      shown that ethanol inhibition of NMDAR involves alterations in gating, especially 
      a reduction in mean open time. However, a full description of ethanol's effects 
      on NMDAR kinetics, including fitting them to a kinetic model, has not been 
      reported. METHODS: To determine ethanol's effects on NMDAR kinetics, we used 
      steady-state single-channel recording in outside-out patches from HEK-293 cells 
      transfected with recombinant GluN1/GluN2A or GluN1/GluN2B NMDAR subunits. Very 
      low glutamate concentrations were used to isolate individual activations of the 
      receptor. RESULTS: In both subunit types, ethanol, at approximate whole-cell 
      IC(50) values (156 mM, GluN2A; 150 mM, GluN2B), reduced open probability (p(o) ) 
      by approximately 50% and decreased mean open time without changing the frequency 
      of opening. Open and shut time distributions exhibited two and five components, 
      respectively; ethanol selectively decreased the time constant and relative 
      proportion of the longer open time component. In the GluN2A subunit, ethanol 
      increased the time constants of all but the longest shut time components, whereas 
      in the GluN2B subunit, shut times were unchanged by ethanol. Fitting of bursts of 
      openings (representing individual activations of the receptor) to the gating 
      portion of a kinetic model revealed that ethanol altered two rates: the rate 
      associated with activation of the GluN2A or GluN2B subunit, and the rate 
      associated with the closing of the longer of the two open states. CONCLUSIONS: 
      These results demonstrate that ethanol selectively alters individual kinetic 
      rates and thus appears to selectively affect distinct conformational transitions 
      involved in NMDAR gating.
CI  - (c) 2022 Research Society on Alcoholism.
FAU - Peoples, Robert W
AU  - Peoples RW
AUID- ORCID: 0000-0003-1593-3586
AD  - Department of Biomedical Sciences, Marquette University, Milwaukee, Wisconsin, 
      USA.
FAU - Ren, Hong
AU  - Ren H
AD  - Biobank, Union Hospital, Tongji Medical College, Huazhong University of Science 
      and Technology, Wuhan, China.
LA  - eng
GR  - R03 AA028903/AA/NIAAA NIH HHS/United States
GR  - R01 AA015203/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20221109
PL  - England
TA  - Alcohol Clin Exp Res
JT  - Alcoholism, clinical and experimental research
JID - 7707242
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3K9958V90M (Ethanol)
RN  - 3KX376GY7L (Glutamic Acid)
SB  - IM
MH  - Humans
MH  - *Receptors, N-Methyl-D-Aspartate
MH  - *Ethanol/pharmacology
MH  - Ion Channel Gating
MH  - HEK293 Cells
MH  - Glutamic Acid
PMC - PMC9771960
MID - NIHMS1846124
OTO - NOTNLM
OT  - N-methyl-D-aspartate receptor
OT  - ion channel gating
OT  - kinetic model
OT  - single-channel
EDAT- 2022/10/29 06:00
MHDA- 2022/12/21 06:00
PMCR- 2023/12/01
CRDT- 2022/10/28 05:22
PHST- 2022/10/20 00:00 [revised]
PHST- 2022/03/07 00:00 [received]
PHST- 2022/10/24 00:00 [accepted]
PHST- 2022/10/29 06:00 [pubmed]
PHST- 2022/12/21 06:00 [medline]
PHST- 2022/10/28 05:22 [entrez]
PHST- 2023/12/01 00:00 [pmc-release]
AID - 10.1111/acer.14965 [doi]
PST - ppublish
SO  - Alcohol Clin Exp Res. 2022 Dec;46(12):2203-2213. doi: 10.1111/acer.14965. Epub 
      2022 Nov 9.