title: Unresponsive correlated motion in alpha7 nAChR to halothane binding explains its functional insensitivity to volatile anesthetics.
abstract: Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated as targets for general anesthetics, but the functional responses to anesthetic modulation vary considerably among different subtypes of nAChRs. Inhaled general anesthetics, such as halothane, could effectively inhibit the channel activity of the alpha4beta2 nAChR but not the homologous alpha7 nAChR. To understand why alpha7 is insensitive to inhaled general anesthetics, we performed multiple sets of 20 ns molecular dynamics (MD) simulations on the closed- and open-channel alpha7 in the absence and presence of halothane and critically compared the results with those from our studies on the alpha4beta2 nAChR (Liu et al. J. Phys. Chem. B 2009, 113, 12581 and Liu et al. J. Phys. Chem. B 2010, 114, 626). Several halothane binding sites with fairly high binding affinities were identified in both closed- and open-channel alpha7, suggesting that a lack of sensitive functional responses of the alpha7 nAChR to halothane in the previous experiments was unlikely due to a lack of halothane interaction with alpha7. The binding affinities of halothane in alpha7 seemed to be protein conformation-dependent. Overall, halothane affinity was higher in the closed-channel alpha7. Halothane binding to alpha7 did not induce profound changes in alpha7 structure and dynamics that could be related to the channel function. In contrast, correlated motion of the open-channel alpha4beta2 was reduced substantially in the presence of halothane, primarily due to the more susceptible nature of beta2 to anesthetic modulation. The amphiphilic extracellular and transmembrane domain interface of the beta2 subunit is attractive to halothane and is susceptible to halothane perturbation, which may be why alpha4beta2 is functionally more sensitive to halothane than alpha7.
authors.affiliation: Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: David
authors.initials: D
authors.lastname: Mowrey
authors.forename: Esmael J
authors.initials: EJ
authors.lastname: Haddadian
authors.forename: Lu Tian
authors.initials: LT
authors.lastname: Liu
authors.forename: Dan
authors.initials: D
authors.lastname: Willenbring
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Pei
authors.initials: P
authors.lastname: Tang
mesh_terms: D018685:Anesthetics, Inhalation / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D006221:Halothane / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000378:metabolism; D014101:Torpedo; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D018685:Anesthetics, Inhalation; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D006221:Halothane
references.citation: Neuron. 2004 Mar 25;41(6):907-14
references.pmid: 15046723
references.citation: Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W610-4
references.pmid: 15215461
references.citation: Anesthesiology. 1997 Apr;86(4):859-65
references.pmid: 9105230
references.citation: J Gen Physiol. 2004 Apr;123(4):341-56
references.pmid: 15051806
references.citation: Biophys J. 2003 Nov;85(5):3007-18
references.pmid: 14581202
references.citation: J Mol Graph. 1996 Dec;14(6):354-60, 376
references.pmid: 9195488
references.citation: Biochemistry. 2003 Nov 25;42(46):13457-67
references.pmid: 14621991
references.citation: EMBO J. 2005 Apr 20;24(8):1512-22
references.pmid: 15791209
references.citation: EMBO J. 2009 Oct 7;28(19):3040-51
references.pmid: 19696737
references.citation: Biophys J. 2007 Sep 15;93(6):1895-905
references.pmid: 17513367
references.citation: Fold Des. 1997;2(3):173-81
references.pmid: 9218955
references.citation: Pharmacol Ther. 2006 Sep;111(3):729-70
references.pmid: 16483665
references.citation: J Biol Chem. 2005 Mar 4;280(9):8443-51
references.pmid: 15591050
references.citation: J Neurosci. 2009 Mar 11;29(10):3189-99
references.pmid: 19279256
references.citation: Biophys J. 2008 Mar 1;94(5):1681-8
references.pmid: 17993502
references.citation: J Phys Chem B. 2007 Dec 27;111(51):14186-92
references.pmid: 18052271
references.citation: J Physiol. 2002 Apr 15;540(Pt 2):425-34
references.pmid: 11956333
references.citation: J Biol Chem. 2003 Sep 5;278(36):34079-83
references.pmid: 12826676
references.citation: J Comput Chem. 2005 Dec;26(16):1781-802
references.pmid: 16222654
references.citation: J Biol Chem. 2009 Sep 4;284(36):24176-84
references.pmid: 19605349
references.citation: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references.pmid: 24889800
references.citation: Nucleic Acids Res. 2003 Jul 1;31(13):3784-8
references.pmid: 12824418
references.citation: J Gen Physiol. 2007 Dec;130(6):547-58
references.pmid: 18040057
references.citation: Biochim Biophys Acta. 2010 Feb;1798(2):161-6
references.pmid: 19715664
references.citation: Biophys J. 2007 Oct 15;93(8):2622-34
references.pmid: 17573436
references.citation: J Mol Biol. 2005 Mar 4;346(4):967-89
references.pmid: 15701510
references.citation: Phys Rev Lett. 1996 Aug 26;77(9):1905-1908
references.pmid: 10063201
references.citation: J Neurosci. 2001 Oct 15;21(20):7993-8003
references.pmid: 11588172
references.citation: Mol Pharmacol. 2001 Apr;59(4):732-43
references.pmid: 11259617
references.citation: Biophys J. 2008 Jun;94(11):4464-72
references.pmid: 18310239
references.citation: N Engl J Med. 2003 May 22;348(21):2110-24
references.pmid: 12761368
references.citation: Proc Biol Sci. 1992 Oct 22;250(1327):11-7
references.pmid: 1281328
references.citation: J Biol Chem. 2002 Mar 22;277(12):10367-73
references.pmid: 11741933
references.citation: J Clin Invest. 2003 Feb;111(4):497-505
references.pmid: 12588888
references.citation: FASEB J. 2005 Apr;19(6):567-76
references.pmid: 15791007
references.citation: J Physiol. 2000 Sep 15;527 Pt 3:515-28
references.pmid: 10990538
references.citation: Nature. 2009 Jan 1;457(7225):115-8
references.pmid: 18987630
references.citation: J Gen Physiol. 2002 Oct;120(4):483-96
references.pmid: 12356851
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):16035-40
references.pmid: 12438684
references.citation: Biochim Biophys Acta. 1997 Jan 14;1323(1):154-62
references.pmid: 9030222
references.citation: Int Rev Neurobiol. 2001;48:141-66
references.pmid: 11526737
references.citation: J Phys Chem B. 2008 Nov 6;112(44):13981-90
references.pmid: 18847252
references.citation: J Mol Biol. 1993 Jun 20;231(4):1049-67
references.pmid: 8515464
references.citation: Bioinformatics. 2005 Jul 1;21(13):2978-87
references.pmid: 15860562
references.citation: Anesthesiology. 1997 Apr;86(4):760-2
references.pmid: 9105218
references.citation: Nature. 2009 Jan 1;457(7225):111-4
references.pmid: 18987633
references.citation: J Biol Chem. 2003 Dec 12;278(50):50151-7
references.pmid: 14525990
references.citation: J Phys Chem B. 2008 Nov 13;112(45):14312-8
references.pmid: 18821786
references.citation: Proteins. 2007 Sep 1;68(4):948-60
references.pmid: 17546671
references.citation: Proc Natl Acad Sci U S A. 2005 May 10;102(19):6813-8
references.pmid: 15857954
references.citation: Nature. 2004 Aug 19;430(7002):896-900
references.pmid: 15318223
references.citation: Biophys J. 1997 Apr;72(4):1676-82
references.pmid: 9083671
references.citation: J Phys Chem B. 2009 Sep 17;113(37):12581-9
references.pmid: 19697903
references.citation: Biophys J. 1999 Aug;77(2):739-46
references.pmid: 10423422
references.citation: J Mol Biol. 2006 Jan 13;355(2):310-24
references.pmid: 16307758
references.citation: J Neurosci. 2009 Jan 28;29(4):918-29
references.pmid: 19176801
references.citation: J Phys Chem B. 2010 Jan 14;114(1):626-32
references.pmid: 20014754
references.citation: Biophys J. 2005 Oct;89(4):2350-6
references.pmid: 16040747