Chemical and Genetic Engineering of Selective Ion Channel-Ligand Interactions

被引：215
作者：
Magnus, Christopher J. [1 ]
Lee, Peter H. [1 ]
Atasoy, Deniz [1 ]
Su, Helen H. [1 ]
Looger, Loren L. [1 ]
Sternson, Scott M. [1 ]
机构：
[1] Howard Hughes Med Inst, Ashburn, VA 20147 USA
来源：
SCIENCE | 2011年 / 333卷 / 6047期
关键词：
NEURONAL NICOTINIC RECEPTOR; IN-VIVO; ACETYLCHOLINE-RECEPTORS; PROTEIN; MUTATIONS; LOOP; DESIGN; DOMAIN; DESENSITIZATION; IDENTIFICATION;
D O I：
10.1126/science.1206606
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
Ionic flux mediates essential physiological and behavioral functions in defined cell populations. Cell type-specific activators of diverse ionic conductances are needed for probing these effects. We combined chemistry and protein engineering to enable the systematic creation of a toolbox of ligand-gated ion channels (LGICs) with orthogonal pharmacologic selectivity and divergent functional properties. The LGICs and their small-molecule effectors were able to activate a range of ionic conductances in genetically specified cell types. LGICs constructed for neuronal perturbation could be used to selectively manipulate neuron activity in mammalian brains in vivo. The diversity of ion channel tools accessible from this approach will be useful for examining the relationship between neuronal activity and animal behavior, as well as for cell biological and physiological applications requiring chemical control of ion conductance.
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收藏
页码：1292 / 1296
页数：5
相关论文
共 39 条
[1]   AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training [J].
Aponte, Yexica ;
Atasoy, Deniz ;
Sternson, Scott M. .
NATURE NEUROSCIENCE, 2011, 14 (03) :351-355
[2]   Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand [J].
Armbruster, Blaine N. ;
Li, Xiang ;
Pausch, Mark H. ;
Herlitze, Stefan ;
Roth, Bryan L. .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (12) :5163-5168
[3]   A FLEX switch targets channelrhodopsin-2 to multiple cell types for imaging and long-range circuit mapping [J].
Atasoy, Deniz ;
Aponte, Yexica ;
Su, Helen Hong ;
Sternson, Scott M. .
JOURNAL OF NEUROSCIENCE, 2008, 28 (28) :7025-7030
[4]   MUTATIONS AT 2 DISTINCT SITES WITHIN THE CHANNEL DOMAIN M2 ALTER CALCIUM PERMEABILITY OF NEURONAL ALPHA-7 NICOTINIC RECEPTOR [J].
BERTRAND, D ;
GALZI, JL ;
DEVILLERSTHIERY, A ;
BERTRAND, S ;
CHANGEUX, JP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (15) :6971-6975
[5]   A chemical switch for inhibitor-sensitive alleles of any protein kinase [J].
Bishop, AC ;
Ubersax, JA ;
Petsch, DT ;
Matheos, DP ;
Gray, NS ;
Blethrow, J ;
Shimizu, E ;
Tsien, JZ ;
Schultz, PG ;
Rose, MD ;
Wood, JL ;
Morgan, DO ;
Shokat, KM .
NATURE, 2000, 407 (6802) :395-401
[6]   Discovery and structure -: Activity relationship of quinuclidine benzamides as agonists of α7 nicotinic acetylcholine receptors [J].
Bodnar, AL ;
Cortes-Burgos, LA ;
Cook, KK ;
Dinh, DM ;
Groppi, VE ;
Hajos, M ;
Higdon, NR ;
Hoffmann, WE ;
Hurst, RS ;
Myers, JK ;
Rogers, BN ;
Wall, TM ;
Wolfe, ML ;
Wong, E .
JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (04) :905-908
[7]   Millisecond-timescale, genetically targeted optical control of neural activity [J].
Boyden, ES ;
Zhang, F ;
Bamberg, E ;
Nagel, G ;
Deisseroth, K .
NATURE NEUROSCIENCE, 2005, 8 (09) :1263-1268
[8]   Opposing effects of molecular volume and charge at the hyperekplexia site α1 (P250) govern glycine receptor activation and desensitization [J].
Breitinger, HG ;
Villmann, C ;
Becker, K ;
Becker, CM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (32) :29657-29663
[9]   Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures [J].
Celie, PHN ;
van Rossum-Fikkert, SE ;
van Dijk, WJ ;
Brejc, K ;
Smit, AB ;
Sixma, TK .
NEURON, 2004, 41 (06) :907-914
[10]   Evidence for a diverse cys-loop ligand-gated ion channel superfamily in early bilateria [J].
Dent, Joseph A. .
JOURNAL OF MOLECULAR EVOLUTION, 2006, 62 (05) :523-535
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