Molecular targets and mechanisms for ethanol action in glycine receptors.
Glycine receptors (GlyRs) are recognized as the primary mediators of neuronal inhibition in the spinal cord, brain stem and higher brain regions known to be sensitive to ethanol. Building evidence supports the notion that ethanol acting on GlyRs causes at least a subset of its behavioral effects and may be involved in modulating ethanol intake. For over two decades, GlyRs have been studied at the molecular level as targets for ethanol action. Despite the advances in understanding the effects of ethanol in vivo and in vitro, the precise molecular sites and mechanisms of action for ethanol in ligand-gated ion channels in general, and in GlyRs specifically, are just now starting to become understood. The present review focuses on advances in our knowledge produced by using molecular biology, pressure antagonism, electrophysiology and molecular modeling strategies over the last two decades to probe, identify and model the initial molecular sites and mechanisms of ethanol action in GlyRs. The molecular targets on the GlyR are covered on a global perspective, which includes the intracellular, transmembrane and extracellular domains. The latter has received increasing attention in recent years. Recent molecular models of the sites of ethanol action in GlyRs and their implications to our understanding of possible mechanism of ethanol action and novel targets for drug development in GlyRs are discussed.
Perkins
Daya I
DI
Alcohol and Brain Research Laboratories, Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
Trudell
James R
JR
Crawford
Daniel K
DK
Alkana
Ronald L
RL
Davies
Daryl L
DL
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D000431:Ethanol / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D018009:Receptors, Glycine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
D018009:Receptors, Glycine; D000431:Ethanol
Anesth Analg. 2007 Feb;104(2):318-24
17242087
Anesthesiology. 2001 Jul;95(1):123-31
11465549
J Pharmacol Exp Ther. 2009 Jul;330(1):198-205
19380602
Neurosci Res. 1995 Nov;23(4):377-82
8602277
Alcohol Alcohol. 2007 Jan-Feb;42(1):11-8
17098748
Undersea Hyperb Med. 1996 Mar;23(1):35-41
8653064
Adv Biochem Psychopharmacol. 1992;47:335-47
1354918
J Biol Chem. 1998 Feb 6;273(6):3314-9
9452448
J Chem Inf Model. 2007 Jul-Aug;47(4):1572-9
17602605
J Pharmacol Exp Ther. 2002 Mar;300(3):967-75
11861805
Neuropharmacology. 2003 Mar;44(4):493-502
12646286
Brain Res. 1988 Jul 12;455(2):377-80
2900060
Proteins. 2008 May 1;71(2):972-81
18004757
Amino Acids. 2010 Apr;38(4):1051-5
19543795
Nature. 1971 Jun 11;231(5302):368-71
4931002
Anesthesiology. 1978 Feb;48(2):104-10
655442
J Neurochem. 2007 Oct;103(2):580-9
17714449
Sci Signal. 2008 Jul 15;1(28):re7
18632551
Biochim Biophys Acta. 1977 Nov 1;470(3):509-10
921966
Anesth Analg. 2002 Sep;95(3):578-82, table of contents
12198041
J Pharmacol Exp Ther. 2001 Jan;296(1):77-83
11123365
Mol Pharmacol. 1981 May;19(3):432-7
7266466
Pharmacology. 1981;22(3):199-208
7208603
Biochemistry. 1986 Jun 17;25(12):3619-25
3718947
Biophys J. 2007 May 1;92(9):3159-65
17293400
J Mol Biol. 2000 Sep 29;302(4):955-77
10993735
J Biol Chem. 2005 Jan 7;280(1):308-16
15522868
Biochemistry. 1995 Jul 11;34(27):8564-75
7612598
Pharmacol Biochem Behav. 1995 Feb;50(2):199-205
7740058
Proc Natl Acad Sci U S A. 1998 May 26;95(11):6504-9
9600996
Mol Pharmacol. 1996 Aug;50(2):402-6
8700149
Neurosci Lett. 2004 Nov 23;371(2-3):230-4
15519763
J Biol Chem. 2006 Dec 22;281(51):39300-7
17040914
Pharmacol Ther. 1997;73(2):121-46
9131721
J Neurochem. 2008 Aug;106(3):1337-49
18485105
Nat Rev Neurosci. 2002 Feb;3(2):102-14
11836518
Mol Pharmacol. 1994 Dec;46(6):1156-9
7808436
Br J Pharmacol. 1996 May;118(2):378-84
8735641
Eur J Pharmacol. 1998 Aug 7;354(2-3):239-44
9754925
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8546-51
16581914
J Neurosci. 2006 Feb 8;26(6):1749-58
16467523
Mol Pharmacol. 2001 Sep;60(3):584-94
11502891
Alcohol Clin Exp Res. 2001 Aug;25(8):1098-106
11505039
Pharmacol Rev. 1972 Dec;24(4):583-655
4565956
Biochemistry. 1995 Jul 11;34(27):8576-88
7612599
Arch Pediatr Adolesc Med. 2006 May;160(5):473-8
16651488
Neuropharmacology. 2006 Feb;50(2):174-81
16225893
Alcohol. 2007 May;41(3):211-21
17591544
Drug Alcohol Depend. 1995 May;38(2):155-71
7671767
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15218-23
14625373
Nature. 1984 Aug 16-22;310(5978):599-601
6462249
Mol Pharmacol. 1999 Oct;56(4):768-74
10496960
Mol Pharmacol. 1984 Jan;25(1):123-30
6546781
J Biol Chem. 2001 Apr 20;276(16):12556-64
11278873
J Biol Chem. 2008 Oct 10;283(41):27698-27706
18658152
Life Sci. 1988;43(24):1973-82
3210897
Nature. 1997 Sep 25;389(6649):334-5
9311772
Biochim Biophys Acta. 1973 Jan 26;291(2):321-7
4347901
Nature. 2007 Jan 4;445(7123):116-9
17167423
J Biol Chem. 2002 Nov 8;277(45):43002-10
12226083
J Pharmacol Exp Ther. 1990 Jun;253(3):1229-35
2359024
J Biol Chem. 1992 Jan 25;267(3):1426-9
1346133
Neuropharmacology. 2010 Mar;58(3):676-81
19913039
J Biol Chem. 2004 Feb 6;279(6):4887-93
14610076
EMBO J. 1991 Sep;10(9):2401-9
1651228
Nature. 2003 Jan 16;421(6920):272-5
12529644
J Biol Chem. 1993 Oct 25;268(30):22802-8
8226790
J Neurophysiol. 2004 Jun;91(6):2685-95
14762156
Alcohol Clin Exp Res. 1999 Oct;23(10):1563-70
10549986
Pharmacol Rev. 1989 Dec;41(4):489-537
2700603
Eur J Pharmacol. 1994 Sep 22;263(1-2):25-9
7821359
Neuroscience. 1988 May;25(2):613-24
2840602
Annu Rev Pharmacol Toxicol. 1989;29:365-402
2543272
J Pharmacol Exp Ther. 1996 Apr;277(1):411-6
8613949
J Neurophysiol. 2003 Feb;89(2):806-13
12574458
J Neurosci. 2004 Sep 22;24(38):8379-82
15385620
Trends Pharmacol Sci. 1992 Jul;13(7):291-6
1380742
J Neurochem. 2006 Feb;96(3):885-92
16405501
J Neurophysiol. 2007 May;97(5):3806-11
17376852
Trends Pharmacol Sci. 2005 Oct;26(10):503-10
16126282
Alcohol. 2007 May;41(3):155-62
17521845
Br J Pharmacol. 1989 Jan;96(1):9-16
2784337
Anesthesiology. 2001 Aug;95(2):470-7
11506122
J Biol Chem. 2009 Oct 2;284(40):27304-14
19656948
J Clin Psychiatry. 2001;62 Suppl 20:4-10
11584874
Psychopharmacology (Berl). 1999 Feb;141(4):339-50
10090641
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20523-8
19074265
Brain Res. 2003 Feb 14;963(1-2):165-77
12560122
Pharmacol Biochem Behav. 1982 Feb;16(2):341-6
7071084
Prog Neurobiol. 1991;36(3):171-94
1673253
Trends Neurosci. 1995 Mar;18(3):121-7
7754520
Alcohol Clin Exp Res. 1994 Oct;18(5):1190-5
7847605
Alcohol Clin Exp Res. 2006 Feb;30(2):349-58
16441284
J Pharmacol Exp Ther. 1994 Jul;270(1):61-9
8035343
Brain Res. 1990 Jan 22;507(2):332-6
2186844
Alcohol Clin Exp Res. 1992 Feb;16(1):17-22
1558298
J Pharmacol Exp Ther. 2009 Dec;331(3):933-9
19773530
J Pharm Pharmacol. 1983 May;35(5):306-11
6134799
Drug Alcohol Depend. 2004 Jun 11;74(3):223-34
15194200
J Biol Chem. 2004 Mar 19;279(12):11198-205
14715650
J Biol Chem. 1999 Aug 13;274(33):23006-12
10438467
Nat Neurosci. 2005 Mar;8(3):339-45
15696164
J Pharmacol Exp Ther. 1996 Feb;276(2):667-75
8632335
J Mol Biol. 2005 Mar 4;346(4):967-89
15701510
Trends Neurosci. 1991 Oct;14(10):458-61
1722365
Proc Natl Acad Sci U S A. 1994 Aug 16;91(17):8200-4
8058780
Biochemistry. 1985 May 21;24(11):2624-32
4027217
Nature. 2001 May 17;411(6835):269-76
11357122
J Physiol. 1995 Mar 15;483 ( Pt 3):613-9
7776247
Nature. 1994 Feb 17;367(6464):607-14
7509043
Alcohol Clin Exp Res. 1993 Oct;17(5):935-9
8279677
Cell Mol Life Sci. 2001 May;58(5-6):760-93
11437237
J Neurophysiol. 1997 Mar;77(3):1306-12
9084598
Annu Rev Pharmacol Toxicol. 2000;40:431-58
10836143
Trends Pharmacol Sci. 1997 Nov;18(11):425-9
9426470
J Neurophysiol. 2003 Aug;90(2):870-5
12702707
J Neurophysiol. 1993 Oct;70(4):1339-49
7506753
J Neurosci. 2009 Jan 14;29(2):543-9
19144854
Ann N Y Acad Sci. 1991;625:54-70
2058905
Mol Pharmacol. 1980 Jul;18(1):84-90
7412765
Annu Rev Pharmacol Toxicol. 1979;19:159-78
378102
Alcohol. 2007 May;41(3):145-53
17521846
Eur J Pharmacol. 2003 May 23;469(1-3):37-45
12782183
Prog Neurobiol. 1988;30(4):271-307
2449704
Anesth Analg. 2003 Jan;96(1):97-101, table of contents
12505932
Neuropharmacology. 2002 Sep;43(4):788-98
12367623
Mol Pharmacol. 2000 May;57(5):932-9
10779376
J Neurophysiol. 2001 Nov;86(5):2426-34
11698532
J Pharmacol Exp Ther. 2006 Mar;316(3):1360-8
16272217
Brain Res. 1989 Jun 5;489(1):93-100
2545309
Nature. 1982 Dec 9;300(5892):487-93
6755267
Physiol Chem Phys. 1982;14(2):157-64
7184036
Biochemistry. 2006 Feb 21;45(7):2014-26
16475790
Life Sci. 1978 Jan;22(3):239-44
622002
J Neurochem. 2004 Aug;90(4):962-9
15287902
Subst Alcohol Actions Misuse. 1982;3(1-2):41-6
7135157
Nature. 1975 Oct 30;257(5529):811-3
241941
Psychopharmacology (Berl). 2001 Oct;157(4):401-10
11605100
J Neurosci. 2001 Apr 15;21(8):2589-99
11306612
Alcohol Clin Exp Res. 2005 Jan;29(1):27-37
15654288
Nature. 2009 Jan 1;457(7225):115-8
18987630
J Pharmacol Exp Ther. 1989 Oct;251(1):164-8
2552072
Mol Pharmacol. 2005 Nov;68(5):1291-300
16103045
Undersea Biomed Res. 1974 Mar;1(1):1-28
4619860
Nature. 1992 Jan 23;355(6358):371-3
1731252
J Pharmacol Exp Ther. 1996 Aug;278(2):732-40
8768725
Pharmacol Biochem Behav. 1985 Aug;23(2):309-16
4059316
Dig Dis. 2005;23(3-4):214-21
16508285
Alcohol Clin Exp Res. 2002 Jun;26(6):773-8
12068244
Nature. 1997 Sep 25;389(6649):385-9
9311780
Nature. 1987 Jul 9-15;328(6126):113-4
3600786
Br J Pharmacol. 1996 Dec;119(7):1331-6
8968539
Brain Res. 2009 Dec 11;1305 Suppl:S27-36
19781529
Proc Natl Acad Sci U S A. 1984 Sep;81(17):5412-6
6591197
Physiol Rev. 1982 Oct;62(4 Pt 1):1341-77
6127740
J Neurochem. 2004 Jun;89(5):1175-85
15147510
J Neurochem. 1991 Aug;57(2):384-90
1712827
J Pharmacol Exp Ther. 1981 Jun;217(3):770-5
7230006
Anesthesiology. 2001 Jun;94(6):1026-33
11465594
J Neurophysiol. 2000 Nov;84(5):2409-16
11067983
Neurochem Int. 1999 Aug;35(2):143-52
10405998
Nature. 2008 Sep 25;455(7212):473-4
18818642
J Pharmacol Exp Ther. 2003 Oct;307(1):42-52
14500778
Agents Actions. 1987 Aug;21(3-4):320-2
3687588
Curr Pharm Des. 2007;13(23):2350-67
17692006
Brain Res Mol Brain Res. 2004 Jun 18;125(1-2):86-95
15193425
J Comp Neurol. 2005 Feb 7;482(2):123-41
15611994
J Chem Inf Model. 2005 Jan-Feb;45(1):128-35
15667138
Nature. 2009 Jan 1;457(7225):111-4
18987633
Biochim Biophys Acta. 1973 Jan 26;291(2):328-34
4347902
Life Sci. 1988;43(26):2221-9
3210903
Anesth Analg. 2001 Jan;92(1):123-7
11133613
Alcohol Clin Exp Res. 1998 Nov;22(8):1689-97
9835282
Mol Pharmacol. 1981 Jan;19(1):49-55
7207463
Biochim Biophys Acta. 1980 Jun 20;599(1):336-40
7397157
J Pharmacol Exp Ther. 1993 Oct;267(1):522-37
8229784
Alcohol Clin Exp Res. 1995 Jun;19(3):693-700
7573795
Proc Soc Exp Biol Med. 1954 Jan;85(1):144-9
13134316
Alcohol Alcohol Suppl. 1987;1:139-45
3426670
J Neurochem. 1993 Apr;60(4):1548-53
7681105
Biochim Biophys Acta. 1972 Jan 17;255(1):171-7
5010992
Biophys J. 1999 Nov;77(5):2563-74
10545357
J Pharmacol Exp Ther. 1999 May;289(2):774-80
10215652
Neuropharmacology. 2002 Sep;43(4):607-18
12367606
Int Rev Neurobiol. 2005;65:53-87
16140053
Neuropharmacology. 2008 Oct;55(5):835-43
18639563
Psychopharmacology (Berl). 1982;77(1):11-6
6812114
Nat Neurosci. 2007 Jan;10(1):40-8
17159992
J Biomol Struct Dyn. 1995 Feb;12(4):725-54
7779297
Anesthesiology. 2000 Oct;93(4):1095-101
11020766
Ann N Y Acad Sci. 1992 Jun 28;654:61-9
1321582
J Gen Physiol. 2004 Apr;123(4):341-56
15051806
Proc Natl Acad Sci U S A. 2006 May 30;103(22):8540-5
16698930
J Pharmacol Exp Ther. 2002 Feb;300(2):526-34
11805213
J Chem Inf Model. 2008 Feb;48(2):344-9
18197653
J Biol Chem. 2004 Aug 6;279(32):33919-27
15169788
Fed Proc. 1977 Apr;36(5):1663-7
191296
Protein Eng. 2002 Jun;15(6):443-54
12082162
Br J Anaesth. 1978 Nov;50(11):1091-7
718777
J Neurochem. 2007 Sep;102(6):2097-2109
17561937
Physiol Rev. 2004 Oct;84(4):1051-95
15383648
Alcohol Clin Exp Res. 2004 Feb;28(2):217-27
15112929
Brain Res Mol Brain Res. 1997 Oct 3;49(1-2):63-70
9387864
J Mol Biol. 1995 Feb 17;246(2):317-30
7869383
Undersea Biomed Res. 1979 Mar;6(1):47-53
223266
Life Sci. 1976 Mar 1;18(5):489-97
1256249
J Neurochem. 2010 Jan;112(1):307-17
19878433
Neuropharmacology. 2005 Aug;49(2):243-53
15993446
J Biol Chem. 2006 Feb 10;281(6):3305-11
16361257
Nature. 2009 Nov 26;462(7272):420-1
19940907
J Neurosci. 2001 Mar 15;21(6):RC136
11245705
J Appl Physiol Respir Environ Exerc Physiol. 1979 Apr;46(4):756-65
457554
Alcohol Clin Exp Res. 2003 May;27(5):743-55
12766618
Science. 2004 May 7;304(5672):884-7
15131310
Mol Pharmacol. 1973 Mar;9(2):131-43
4711696
Sci STKE. 2005 Nov 08;2005(309):re14
16278489
Annu Rev Pharmacol Toxicol. 1984;24:43-64
6329077
J Gen Physiol. 2007 Dec;130(6):569-79
18040059
J Neurochem. 2008 Mar;104(6):1649-62
18036150
Alcohol Clin Exp Res. 1998 Aug;22(5):1132-6
9726286
Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9305-10
10908659
Neurosci Lett. 1998 Feb 6;242(1):25-8
9509996
Science. 1950 Jul 21;112(2899):91-2
15442245