title: Desensitization of alpha7 nicotinic receptor is governed by coupling strength relative to gate tightness.
abstract: Binding of a neurotransmitter to its membrane receptor opens an integral ion conducting pore. However, prolonged exposure to the neurotransmitter drives the receptor to a refractory state termed desensitization, which plays an important role in shaping synaptic transmission. Despite intensive research in the past, the structural mechanism of desensitization is still elusive. Using mutagenesis and voltage clamp in an oocyte expression system, we provide several lines of evidence supporting a novel hypothesis that uncoupling between binding and gating machinery is the underlying mechanism for α7 nicotinic receptor (nAChR) desensitization. First, the decrease in gate tightness was highly correlated to the reduced desensitization. Second, nonfunctional mutants in three important coupling loops (loop 2, loop 7, and the M2-M3 linker) could be rescued by a gating mutant. Furthermore, the decrease in coupling strength in these rescued coupling loop mutants reversed the gating effect on desensitization. Finally, coupling between M1 and hinge region of the M2-M3 linker also influenced the receptor desensitization. Thus, the uncoupling between N-terminal domain and transmembrane domain, governed by the balance of coupling strength and gate tightness, underlies the mechanism of desensitization for the α7 nAChR.
authors: Division of Neurobiology, Barrow Neurological Institute and St. Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
authors: Jianliang
authors: J
authors: Zhang
authors: Fenqin
authors: F
authors: Xue
authors: Paul
authors: P
authors: Whiteaker
authors: Chaokun
authors: C
authors: Li
authors: Wen
authors: W
authors: Wu
authors: Benchang
authors: B
authors: Shen
authors: Yao
authors: Y
authors: Huang
authors: Ronald J
authors: RJ
authors: Lukas
authors: Yongchang
authors: Y
authors: Chang
references: Mol Pharmacol. 2004 Jul;66(1):169-77
references: 15213309
references: Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5030-3
references: 8506347
references: J Biol Chem. 2006 Jun 30;281(26):18184-92
references: 16595655
references: J Gen Physiol. 1998 Aug;112(2):181-97
references: 9689026
references: Neuron. 1995 Jul;15(1):181-91
references: 7542462
references: Neurosci Lett. 2008 Jan 31;431(2):184-9
references: 18162311
references: Nature. 1995 Aug 10;376(6540):514-6
references: 7637783
references: Nature. 2005 Nov 10;438(7065):243-7
references: 16281039
references: Proc Natl Acad Sci U S A. 2001 Jan 30;98(3):1241-8
references: 11158624
references: J Physiol. 1957 Aug 29;138(1):63-80
references: 13463799
references: Trends Neurosci. 2005 Jul;28(7):371-8
references: 15979501
references: J Biol Chem. 2005 Feb 25;280(8):6642-7
references: 15611071
references: J Biol Chem. 2008 Dec 19;283(51):35638-43
references: 18952603
references: J Neurobiol. 2002 Dec;53(4):457-78
references: 12436413
references: Nature. 1991 Oct 31;353(6347):846-9
references: 1719423
references: J Biol Chem. 2004 Feb 6;279(6):4887-93
references: 14610076
references: Nature. 2003 Jan 16;421(6920):272-5
references: 12529644
references: J Physiol. 2003 Dec 15;553(Pt 3):857-71
references: 14555718
references: Neuron. 1998 Nov;21(5):959-80
references: 9856454
references: Proc Natl Acad Sci U S A. 1992 Feb 15;89(4):1261-5
references: 1741378
references: Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):6118-23
references: 8650229
references: Nature. 2003 Jun 26;423(6943):949-55
references: 12827192
references: J Biol Chem. 2006 Aug 4;281(31):21781-21788
references: 16754678
references: J Biol Chem. 2005 Dec 16;280(50):41655-66
references: 16216879
references: J Physiol. 2009 Jan 15;587(1):139-53
references: 19015197
references: Nature. 2005 Dec 15;438(7070):975-80
references: 16355215
references: Acta Pharmacol Sin. 2009 Jun;30(6):663-72
references: 19444220
references: J Neurosci. 2002 Sep 15;22(18):7982-90
references: 12223551
references: J Mol Biol. 1993 Feb 20;229(4):1101-24
references: 8445638
references: Mol Pharmacol. 1998 Mar;53(3):511-23
references: 9495819
references: J Physiol. 2010 Nov 15;588(Pt 22):4415-29
references: 20837638
references: Nature. 2009 Jan 1;457(7225):115-8
references: 18987630
references: Nature. 1980 Jul 3;286(5768):71-3
references: 6248795
references: Annu Rev Pharmacol Toxicol. 2010;50:1-38
references: 20055696
references: Nature. 1995 Jan 5;373(6509):37-43
references: 7800037
references: Cell Mol Neurobiol. 1989 Jun;9(2):141-78
references: 2663167
references: Science. 1984 Sep 21;225(4668):1335-45
references: 6382611
references: Nat Neurosci. 2002 Nov;5(11):1163-8
references: 12368804
references: Mol Pharmacol. 2008 Oct;74(4):941-51
references: 18599601
references: Biochemistry. 2001 Feb 20;40(7):2066-74
references: 11329274
references: Nature. 2009 Jan 1;457(7225):111-4
references: 18987633
references: J Physiol. 2008 Feb 15;586(4):1105-15
references: 18096596
references: Nature. 2008 Aug 7;454(7205):722-7
references: 18633353
references: J Neurosci. 2008 Jul 30;28(31):7808-19
references: 18667613
references: Science. 1995 Apr 14;268(5208):307-10
references: 7716527
references: Nature. 2004 Aug 19;430(7002):896-900
references: 15318223
references: J Gen Physiol. 2005 Jul;126(1):23-39
references: 15955875
references: Prog Biophys Mol Biol. 2004 Oct;86(2):161-204
references: 15288758
references: Biophys J. 2006 Jul 15;91(2):705-14
references: 16648164
references: J Neurosci. 1997 Aug 1;17(15):5747-59
references: 9221773