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Activation and Regulation of Purinergic P2X Receptor Channels 0031-6997/11/6303-641–683$25.00 PHARMACOLOGICAL REVIEWS Vol. 63, No. 3 U.S. Government work not protected by U.S. copyright 3129/3686585 Pharmacol Rev 63:641–683, 2011 Printed in U.S.A. ASSOCIATE EDITOR: DAVID R. SIBLEY Activation and Regulation of Purinergic P2X Receptor Channels Claudio Coddou, Zonghe Yan, Tomas Obsil, J. Pablo Huidobro-Toro, and Stanko S. Stojilkovic Section on Cellular Signaling, Program in Developmental Neuroscience, National Institute of Child Health and Human Development, Downloaded from National Institutes of Health, Bethesda, Maryland (C.C., Z.Y., S.S.S.); Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic (T.O.); and Centro de Envejecimiento y Regeneracio´n, Centro Regulacio´n Celular y Patología Prof. J.V. Luco, Instituto Milenio de Biología Fundamental y Aplicada, Departamento de Fisiología, Facultad de Ciencias Biolo´gicas, P. Universidad Cato´lica de Chile, Santiago, Chile (J.P.H.-T.) pharmrev.aspetjournals.org Abstract ................................................................................ 642 I. Introduction............................................................................. 642 II. Molecular and crystal structure of p2X2 receptors .......................................... 644 III. Orthosteric binding sites and receptor function ............................................. 647 A. P2X receptor agonism and antagonism ................................................. 647 1. Homomeric P2X1 receptor .......................................................... 648 2. Homomeric P2X2 receptor and heteromeric P2X1/2 receptor ............................. 650 3. Homomeric P2X3 receptor and heteromeric P2X2/3 receptor ............................. 652 at Pontificia Univ Catolica de Chile Sistema Biblio MED on May 23, 2016 4. Homomeric P2X4 receptor and heteromeric P2X1/4 receptor ............................. 654 5. Homomeric P2X5 receptor and heteromeric P2X1/5 receptor ............................. 656 6. Homomeric P2X6 receptor and heteromeric P2X2/6 and P2X4/6 receptors.................. 657 7. Homomeric P2X7 receptor .......................................................... 658 B. Ligand binding domain ............................................................... 661 1. Identification of residues contributing to ATP binding................................. 661 2. Number of occupied binding sites necessary to channel activation ...................... 662 3. Orthosteric sites in the context of the P2X4.1 structure.................................... 662 IV. Allosteric binding sites and receptor function............................................... 664 A. Metals as allosteric modulators ........................................................ 664 1. Essential trace metals ............................................................. 664 a. P2X1, P2X3, and P2X5 receptors ................................................. 664 b. P2X2 receptor .................................................................. 664 c. P2X4 receptor .................................................................. 665 d. P2X7 receptor .................................................................. 666 e. Other P2X receptors ............................................................ 666 f. Summary ...................................................................... 666 2. Heavy metals ..................................................................... 666 3. Lanthanides ...................................................................... 667 4. Macro metals ..................................................................... 667 B. Protons as allosteric modulators ....................................................... 668 C. Ivermectin as the P2X4 receptor-specific modulator ...................................... 669 D. Alcohols influence P2X receptor gating ................................................. 670 E. Roles of protein kinases in regulation of P2X receptor function............................ 671 F. Regulation of P2X receptors by lipids................................................... 671 G. Multiple roles of steroid hormones on P2X receptor function .............................. 672 H. Other modulators .................................................................... 673 1. Reactive oxygen species ............................................................ 673 2. Carbon monoxide .................................................................. 673 Address correspondence to: Dr. Stanko Stojilkovic, Section on Cellular Signaling, PDN, NICHD, National Institutes of Health, Bldg. 49, Room 6A36, Bethesda, MD 20892-4510. E-mail: [email protected] or [email protected] This article is available online at http://pharmrev.aspetjournals.org. doi:10.1124/pr.110.003129. 641 642 CODDOU ET AL. 3. Cibacron blue 3GA ................................................................ 673 4. Propofol, ketamine, and toluene..................................................... 673 5. Tetramethylpyrasine............................................................... 673 V. Future directions ........................................................................ 674 VI. Conclusions ............................................................................. 674 Acknowledgments ....................................................................... 674 References .............................................................................. 675 Abstract——Mammalian ATP-gated nonselective cat- The transmembrane domains account not only for the ion channels (P2XRs) can be composed of seven possible formation of the channel pore but also for the binding subunits, denoted P2X1 to P2X7. Each subunit contains of ivermectin (a specific P2X4R allosteric regulator) a large ectodomain, two transmembrane domains, and and alcohols. The N- and C- domains provide the struc- intracellular N and C termini. Functional P2XRs are tures that determine the kinetics of receptor desensi- organized as homomeric and heteromeric trimers. tization and/or pore dilation and are critical for the This review focuses on the binding sites involved in regulation of receptor functions by intracellular mes- the activation (orthosteric) and regulation (allosteric) sengers, kinases, reactive oxygen species and mer- of P2XRs. The ectodomains contain three ATP binding cury. The recent publication of the crystal structure of sites, presumably located between neighboring sub- the zebrafish P2X4.1R in a closed state provides a ma- units and formed by highly conserved residues. The jor advance in the understanding of this family of detection and coordination of three ATP phosphate receptor channels. We will discuss data obtained from residues by positively charged amino acids are likely numerous site-directed mutagenesis experiments ac- to play a dominant role in determining agonist po- cumulated during the last 15 years with reference to tency, whereas an AsnPheArg motif may contribute to the crystal structure, allowing a structural interpreta- binding by coordinating the adenine ring. Noncon- tion of the molecular basis of orthosteric and alloste- served ectodomain histidines provide the binding ric ligand actions. sites for trace metals, divalent cations, and protons. I. Introduction (Burnstock, 1972) but was received with skepticism un- The potential relevance of extracellular ATP in syn- til the first receptor was cloned in 1993 (Webb et al., aptic transmission was originally introduced in 1972 1993). It is now well established that there are two families of receptors activated by extracellular nucleo- 1Abbreviations: A317491, 5-[[[(3-phenoxyphenyl)methyl][(1S)-1, -2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl]-1,2,4-benzenetricar- trisulfonic acid; NF110, 4,4Ј,4Љ,4ٞ-[carbonylbis[imino-5,1,3-benzenetriyl boxylic acid sodium salt hydrate; A438079, 3-[[5-(2,3-dichlorophenyl)- bis(carbonylimino)]]tetrakisbenzenesulfonic acid tetrasodium salt; NF279, 1H-tetrazol-1-yl]methyl]pyridine hydrochloride; A740003, N-(1-([(cyano- 8,8Ј-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecar- -imino)(5-quinolinylamino) methyl] amino)-2,2-dimethylpropyl)-2-(3, bonylimino)]bis-1,3,5-naphthalenetrisulfonic acid; NF449, 4,4Ј,4Љ,4ٞ 4-dimethoxyphenyl)acetamide; A804598, 2-cyano-1-[(1S)-1-phenylethyl]-3- [carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino))]tetrakis-1, ϭ Ј quinolin-5-ylguanidine; ApnA, diadenosine polyphosphate (where n the 3-benzenedisulfonic acid; NF770, 7,7 -(carbonylbis(imino-3,1-phenylene- number of phosphates); AR, adenosine receptor; ATP␥S, adenosine-5Ј-O- carbonylimino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy- (3-thiotriphosphate); AZ10606120, N-[2-[[2-[(2-hydroxyethyl)amino]ethyl] naphthalene-3,6-disulfonic acid) tetrasodium salt; NF776, 6, amino]-5-quinolinyl]-2-tricyclo[3.3.1.13,7]dec-1-ylacetamide dihydrochlo- 6Ј-(carbonylbis(imino-3,1-(4-methylphenylene)carbonylimino))bis(1- ride; AZ11645373, 3-[1-[[(3Ј-nitro[1,1Ј-biphenyl]-4-yl)oxy]methyl]-3-(4- methoxynaphthalene-3,5-disulfonic acid) tetrasodium salt; NF778, 6,6Ј- pyridinyl)propyl]-2,4-thiazolidinedione; BBG, Coomassie brilliant blue G; (carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methyl-phenylene) BzATP, 2Ј(3Ј)-O-4-benzoylbenzoyl)-ATP; CaM, calmodulin; DRG, dorsal carbonylimino))bis(1-methoxy-naphthalene-3,5-disulfonic acid) tetra- -root ganglion; GW791343, N2-(3,4-difluorophenyl)-N1-((2-methyl-5-(1- sodium salt; NF864, 8,8Ј,8Љ,8ٞ-(carbonylbis(imino-5,1,3-benzenetriyl
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