| Hot Topics |
| The following are recent publications of interest. |
| 2012 | 2011 | 2010 | 2009 | 2008 | 2007 |
| 2012 |
| Crystal structures of the μ and κ opioid receptors |
|
Comments by Brian M. Cox: It is now almost 60 years since Beckett and Casy first proposed that morphine and related drugs must act through a specific receptor in brain to induce analgesia (1), and nearly 40 years since three groups independently showed the presence of high affinity binding sites for such drugs in the central nervous system (2, 3, 4). Another milestone in our understanding of the actions of morphine like drugs comes with the publication this month of the crystal structures of two of the four closely related opioid peptide receptors, the κ opioid receptor (5) and the μ opioid receptor (6). Morphine and other opiates used therapeutically act predominantly through the μ receptor while the κ receptor is activated predominantly by some ketocyclazocines, by the hallucinogenic agent salvinorin A, and by the endogenous opioid dynorphin. The new reports follow closely on reports earlier this year of other GPCRs. The two groups responsible for these latest developments used similar strategies; the receptors were crystallized as complexes with very tightly binding highly receptor-type-selective antagonist ligands; JDTic in the case of the κ receptor and β-FNA for the μ receptor. Thus in each case the receptor is visualized in an inactive conformation. Nevertheless, some interesting features are immediately apparent. Both receptors crystallized as dimers, with more than one potential interface between adjacent receptor monomers as possible dimerization sites. Higher polymerization states and heterodimerization with other GPCRs are possible. These observations provide a structural basis for earlier proposals that opioid receptors might function as dimers or higher polymers (7). Opiate drugs are also known for their rapid reversibility - the immediacy of the reversal of opiate-induced respiratory depression by naloxone can be dramatic. The new studies show that the ligand binding pockets of both the μ and κ receptors are unusually exposed or open relative to other GPCRs. The accessibility of the binding pocket favors rapid dissociation (except in the case of irreversible antagonists such as β-FNA). Since the affinity of many agonist and antagonists at μ or κ receptors is high despite their rapid reversibility, their association rates must also be very high. Another feature of opioid receptors is the apparent ability of different ligands acting through the same receptor type to direct signaling through different effector pathways. Ligands for opioid receptors are chemically very heterogeneous. The reported structures for the μ and κ receptors point to accessory sites around the common ligand binding pocket for each receptor that provide additional points of receptor interaction for some ligands. Much work needs to be done to understand the basis of agonism at these receptors, but it is tempting to speculate that these additional interaction sites for some ligands might be exploited in the design of agonists preferentially driving signaling through alternative transduction pathways. |
| (1) Beckett AH and Casy AF. (1954) Synthetic analgesics: stereochemical considerations. J Pharm Pharmacol. 12: 986-1001. [PMID: 13212680] |
| (2) Pert CB and Snyder SH. (1973) Opiate receptor: demonstration in nervous tissue. Science. 179: 1011-1014. [PMID: 4687585] |
| (3) Simon EJ, Hiller JM, Edelman I. (1973) Stereospecific binding of the potent narcotic analgesic (3H)etorphine to rat brain homogenate. Proc Natl Acad Sci USA. 70: 1947-1949. [PMID: 4516196] |
| (4) Terenius L. (1973) Stereospecific interaction between narcotic analgesics and a synaptic plasma membrane fraction of rat cerebral cortex. Acta Pharmacol Toxicol. 32: 317-320. [PMID: 4801733] |
| (5) Wu H, Wacker D, Mileni M, Katritch V, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. (2012) Structure of the human κ-opioid receptor in complex with JDTic. Nature. doi: 10.1038/nature10939. [Epub ahead of print] [PMID: 22437504] |
| (6) Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. (2012) Crystal structure of the μ-opioid receptor bound to a morphinan antagonist. Nature. doi: 10.1038/nature10954. [Epub ahead of print] [PMID: 22437502] |
| (7) Jordan BA and Devi L. (1999) G-protein-coupled receptor heterodimerization modulates receptor function. Nature. 399: 697-700. [PMID: 10385123] |
| Crystal structure of the S1P1 receptor |
|
Comments by Tony Harmar and Jerold Chun: The structure of the S1P1 receptor fused with T4 lysozyme, in complex with a selective antagonist sphingolipid mimic (ML056), has been reported at 2.8 Å and 3.35 Å resolution by scientists from the Scripps Research Institute and their drug discovery company Receptos (San Diego, CA). This approach that has revealed important structures of other inactive conformations of GPCRs unbound to G proteins. The structure of the ligand-binding pocket of the receptor suggests that there is limited access for ligand from the extracellular surface of the receptor; rather, ligands may gain access to the binding pocket from within the membrane bilayer, as has been proposed for retinal loading into opsin and for the entry of anandamide into cannabinoid receptors. Modeling and site-directed mutagenesis studies led to the mapping of a putative binding pocket for a subclass of agonists that is distinct from the putative binding site for the endogenous ligand. The active metabolite of the S1P1 agonist fingolimod, which actually appears to involve efficacy through functional antagonistic properties on lymphocytes and CNS cells, represents the first oral therapy for multiple sclerosis, and several other compounds are in development that possess S1P1 modulatory activities. Structural data on the critical signaling complex of S1P1 with its biologically relevant heterotrimeric G proteins, as has been reported for the structure of the β2 adrenergic receptor in complex with Gs, await further studies. |
| (1) Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC, Sanna MG, Han GW, Kuhn P, Rosen H, Stevens RC. (2012) Crystal Structure of a Lipid G Protein–Coupled Receptor Science. 335: 851-5. [PMID: 22344443] |
| Structures of M2 and M3 muscarinic acetylcholine receptors |
|
Comments by A.J. Harmar: The structures of the human M2 receptor and the rat M3 receptor, each in a complex with an inverse agonist (3-quinuclidinyl-benzilate and tiotropium, respectively) have been reported (1,2). In each case, the third intracellular loop of the receptor was replaced with T4 lysozyme – an approach that has been used to obtain crystal structures of several other GPCRs. The overall structures of the two receptors are similar, even in some regions (e.g. intracellular and extracellular loops) that display divergent amino acid sequences. In both cases, there is a “large extracellular vestibule as part of an extended hydrophilic channel containing the orthosteric ligand binding site” – a feature that has not been seen in previous GPCR structures. The orthosteric ligand binding sites share many common features with other unrelated acetylcholine binding proteins. Amino acid residues forming the binding pocket are highly conserved between muscarinic receptor subtypes, explaining why receptor subtype specific orthosteric ligands have been difficult to obtain. However, the new structures demonstrate some differences between the binding sites in M2 and M3 receptors that might permit the development of subtype-selective ligands. There are significant differences in the position of the cytoplasmic end of TM5 and of ICL2 between the two receptors, which may contribute to their different G protein coupling specificities: the position of TM5 was similar in the Gi/o coupled M2, D3 and CXCR4 receptors, whereas the Gq/11-coupled M3 and H1 receptors exhibit a different conformation. A better understanding of G protein coupling specificity will require solution of the structures of more receptor – G protein complexes, as has been achieved for the β2 adrenoceptor – Gs complex (3). Simulations of the binding of tiotropium to M2 and M3 receptors showed that the ligand pauses at a known allosteric site during association and dissociation from the receptor, leading the authors to suggest that “conceivably, therapeutic molecules could be rationally engineered to act independently as both allosteric and orthosteric ligands”. |
| (1) Haga K, Kruse AC, Asada H, Yurugi-Kobayashi T, Shiroishi M, Zhang C, Weis WI, Okada T, Kobilka BK, Haga T, Kobayashi T. (2012) Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature. 482: 547-51. [PMID: 22278061] |
| (2) Kruse AC, Hu J, Pan AC, Arlow DH, Rosenbaum DM, Rosemond E, Green HF, Liu T, Chae PS, Dror RO, Shaw DE, Weis WI, Wess J, Kobilka BK. (2012) Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature. 482: 552-6. [PMID: 22358844] |
| (3) Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK. (2011) Crystal structure of the β2 adrenergic receptor-Gs protein complex. Nature. 477: 549-55. [PMID: 21772288] |
| 2011 |
| IUPHAR review article published on the Calcium-Activated Chloride Channels. |
| Huang F, Wong X, Jan LY. (2012) International Union of Basic and Clinical Pharmacology. LXXXV: Calcium-Activated Chloride Channels. Pharmacol Rev. 64: 1-15. [PMID: 22090471] |
| N.B. This family is not currently listed in IUPHAR-DB. See the Guide to Receptors and Channels (GRAC) page on Calcium-Activated Chloride Channels. |
| The 7-transmembrane receptor LGR5: A GPCR no more? |
|
Comments by Elizabeth R. Lawlor and Richard R. Neubig, University of Michigan, Ann Arbor, Michigan LGR5 and its close relatives LGR4 and LGR6 were first identified as a family of structurally distinct 7-transmembrane receptors with homology to glycoprotein hormone receptors. Characterized by large N-terminal extracellular domains comprised of 17 leucine-rich repeats, the ligands and downstream signaling of these receptors have remained a mystery. Two recent papers have now identified secreted R-spondin (RSPO) proteins as ligands for LGR5 and its homologues and have demonstrated that RSPO binding of LGR4/5/6 potentiates canonical Wnt-beta catenin signaling (1,2). LGR5 is a marker of stem cells in the base of intestinal crypts and in hair follicles and has been previously shown to be itself a canonical Wnt target gene in these cells. Moreover, significant data support LGR5+ stem cells as cells of origin for colorectal carcinoma and also implicate LGR5 as a mediator of tumor aggression. The combined data from the Liu and Clevers labs now suggest that by acting as an upstream potentiator of Wnt-beta catenin signaling, LGR5 promotes the proliferation and expansion of stem cell populations. Intriguingly, despite their close identity with FSH, LH and TSH, LGR5 and its homologues do not appear to function as GPCRs. The cumulative data from both groups indicate that RSPO-induced activation of LGR4/5/6 does not signal through G-proteins nor induce beta arrestin translocation. Rather, RSPO-binding of the leucine-rich N-terminal domains leads to an increase in the phosphorylation of the Wnt co-receptor LRP6, thereby upregulating activity of the Frizzled-LRP6 receptor complex and potentiating beta catenin activity. Although it is conceivable that other ligands might exist for LGR5 and its homologues, these recent reports indicate that RSPO-binding of LGR5 maintains stem cell proliferation through Wnt-beta catenin signaling in a manner that is independent of G-protein coupled signaling. |
| (1) Carmon KS, Gong X, Lin Q, Thomas A, Liu Q. (2011) R-spondins function as ligands of the orphan receptors Lgr4 and Lgr5 to regulate Wnt/{beta}-catenin signaling. Proc Natl Acad Sci U S A. 108: 11452-7. [PMID: 21693646] |
| (2) de Lau W, Barker N, Low TY, Koo BK, Li VS, Teunissen H, Kujala P, Haegebarth A, Peters PJ, van de Wetering M, Stange DE, van Es J, Guardavaccaro D, Schasfoort RB, Mohri Y, Nishimori K, Mohammed S, Heck AJ, Clevers H. (2011) Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nature. Published online ahead of print Jul 4 2011. DOI: 10.1038/nature10337. [PMID: 21727895] |
| IUPHAR review article published on the nomenclature, distribution and pathophysiological functions of Leukotriene receptors. |
| Bäck M, Dahlén S-E, Drazen JM, Evans JF, Serhan CN, Shimizu T, Yokomizo T, Rovati GE. (2011) International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions. Pharmacol Rev. 63:539-584 [Abstract] |
| IUPHAR review article published updating the classification of Prostanoid receptors. |
| Woodward DF, Jones RL, Narumiya S. (2011) International Union of Basic and Clinical Pharmacology. LXXXIII: Classification of Prostanoid Receptors, Updating 15 Years of Progress. Pharmacol Rev. 63:471-538 [PMID: 21752876] |
| IUPHAR review article published on the nomenclature and classification of Hydroxy-carboxylic Acid receptors (GPR81, GPR109A and GPR109B). |
| Offermanns S, Colletti SL, Lovenberg TW, Semple G, Wise A, IJzerman AP. (2011) International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B). Pharmacol Rev. 63: 269-90. [PMID: 21454438] |
| IUPHAR review article published on the nomenclature and classification of Adenosine receptors. |
| Fredholm BB, Ijzerman AP, Jacobson KA, Linden J, Müller CE. (2011) International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update. Pharmacol Rev. 63: 1-34. [PMID: 21303899] |
| Progesterone puts a swing in the tail. |
|
Comments by David E. Clapham and John A. Peters: Two recent reports in Nature by Strünker et al. (1) and Lishko et al. (2) have answered a long standing question in reproductive physiology: how does progesterone cause a rapid influx of Ca2+ into human spermatozoa? Using patch-clamp recording from human mature sperm cells (1,2) and optical techniques (1) the Authors provide compelling evidence that progesterone causes the activation and potentiation of a class of calcium selective ion channel that is activated by depolarization and which is expressed exclusively in the testes and sperm, namely the CatSpers (3). CatSpers are assembled as a complex of pore-forming CatSper1-4 subunits in association with CatSperβ, γ and δ auxiliary subunits, all of which are essential for function (4). Intracellular alkalinization of sperm, as occurs in the female reproductive tract, causes the opening of CatSper channels triggering Ca2+ entry and hyperactivation (whip-like flagellar beats) that are necessary for penetration of the egg cumulus and zona pellucida and subsequent fertilization (4). Alkalinization causes a hyperpolarizing shift in the voltage dependency of CatSper opening, an action that the recent reports (1, 2) also find for low nanomolar concentrations of progesterone, which acts in synergy with increased intracellular pH to stimulate CatSper mediated Ca2+ influx. Crucially, all of the evidence points to non-genomic action of progesterone via a cell surface receptor and, furthermore, to one that does not involve second messenger signalling. The molecular target of progesterone remains uncertain: the possibilities include the CatSper complex itself, or an associated protein. These studies (1, 2) expand the list of ion channels that are subject to non-genomic regulation by steroid hormones. They also identify an interesting species difference in sperm regulation, since mouse CatSper activity is not increased by progesterone (2). Mechanistically, it is intriguing that the voltage-dependency of the opening of human and mouse CatSper differs substantially (2). Identifying the receptor for progesterone that modulates CatSper may potentially reveal a target for a novel male contraceptive agent in man. |
| (1) Strünker T, Goodwin N, Brenker C, Kashikar ND, Weyland I, Seifert R. (2011) The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature. 471: 382-386. [PMID: 21412338] |
| (2) Lishko PV, Botchkina IL, Kirichok Y. (2011) Progesterone activates the principal Ca2+ channel of human sperm. Nature. 471: 387-391. [PMID: 21412339] |
| (3) Clapham DE, Garbers DL. (2005) International Union of Pharmacology. L. Nomenclature and structure-function relationships of CatSper and two-pore channels. Pharmacol Rev. 57: 451-454. [PMID: 16382101] |
| Three papers explore the structures of agonist-bound β-adrenoceptors. |
| (1) Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, Rasmussen SG, Choi HJ, Devree BT, Sunahara RK, Chae PS, Gellman SH, Dror RO, Shaw DE, Weis WI, Caffrey M, Gmeiner P, Kobilka BK. (2011) Structure and function of an irreversible agonist-β(2) adrenoceptor complex. Nature. 469: 236-40 [PMID: 21228876] |
| (2) Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, Devree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellman SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK. (2011) Structure of a nanobody-stabilized active state of the β(2) adrenoceptor. Nature. 469: 175-80 [PMID: 21228869] |
| (3) Warne T, Moukhametzianov R, Baker JG, Nehmé R, Edwards PC, Leslie AG, Schertler GF, Tate CG. (2011) The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor. Nature. 469: 241-4 [PMID: 21228877] |
| Commentary in: |
| (4) Sprang SR. (2011) Cell signalling: Binding the receptor at both ends. Nature. 469: 172-3 [PMID: 21228868] |
| (5) Nature news article from 12th January 2011: "Near-action shots of vital proteins". |
| An update paper on IUPHAR-DB is published in the 2011 Nucleic Acids Research Database Issue. |
| Sharman JL, Mpamhanga CP, Spedding M, Germain P, Staels B, Dacquet C, Laudet V, Harmar AJ, and NC-IUPHAR. (2011) IUPHAR-DB: new receptors and tools for easy searching and visualization of pharmacological data. Nucl. Acids Res. 39 (Database Issue): D534-D538. [Abstract] [Full text] |
| 2010 |
| A population-specific HTR2B stop codon predisposes to severe impulsivity. |
|
Comments by A.J. Harmar: Bevilacqua and colleagues (1) identified a single nucleotide polymorphism in the gene encoding the 5-HT2B receptor (HTR2B Q20*) that was significantly associated with impulsivity in a Finnish population of violent offenders and matched controls. The polymorphism, which was only found in Finnish populations, introduces a stop codon into the N-terminal extracellular domain of the receptor, leading to reduced expression of the 5-HT2B receptor protein in the brain. 5-HT2B receptor knockout (Htr2b-/-) mice have reduced viability due to cardiovascular defects, but those that survive have a normal lifespan (2). These mice displayed increased impulsive behaviour, according to several measures. |
| (1) Bevilacqua L, Doly S, Kaprio J, Yuan Q, Tikkanen R, Paunio T, Zhou Z, Wedenoja J, Maroteaux L, Diaz S, Belmer A, Hodgkinson CA, Dell'osso L, Suvisaari J, Coccaro E, Rose RJ, Peltonen L, Virkkunen M, Goldman D. (2010) A population-specific HTR2B stop codon predisposes to severe impulsivity. Nature. 468: 1061-1066. [PMID: 21179162] |
| (2) Nebigil CG, Choi DS, Dierich A, Hickel P, Le Meur M, Messaddeq N, Launay JM, Maroteaux L. (2000) Serotonin 2B receptor is required for heart development. Proc Natl Acad Sci U S A. 97: 9508-9513 [PMID: 10944220] |
| Crystal structure of the human dopamine D3 receptor in complex with the small molecule D2/D3-specific antagonist eticlopride. |
| Chien EYT, Liu W, Zhao Q, Katritch V, Won Han G, Hanson MA, Shi L, Hauck Newman A, Javitch JA, Cherezov V, Stevens RC. (2010) Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist. Science. 330 (6007): 1091-1095; DOI: 10.1126/science.1197410. [Abstract] [Full text] |
| IUPHAR review article published on the nomenclature, distribution and function of the Kisspeptin receptor. |
| Kirby HR, Maguire JJ, Colledge WH, Davenport AP. (2010) International Union of Basic and Clinical Pharmacology. LXXVII. Kisspeptin Receptor Nomenclature, Distribution, and Function. Pharmacol Rev. 62 (4): 565-78. [PMID:21079036] |
| IUPHAR review article published on the nomenclature of Lysophospholipid receptors. |
| Chun J, Hla T, Lynch KR, Spiegel S, Moolenaar WH. (2010) International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature. Pharmacol Rev. 62 (4): 579-87. [PMID:21079037] |
| IUPHAR review article published on the nomenclature and pharmacology of Cannabinoid receptors. |
| Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, Greasley PJ, Hansen HS, Kunos G, Mackie K, Mechoulam R, Ross RA. (2010) International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1 and CB2. Pharmacol Rev. 62 (4): 588-631. [PMID:21079038] |
| IUPHAR review article published on the structure, signalling, accessory proteins, receptor dynamics and pharmacology of Frizzled class receptors. |
| Schulte G. (2010) International Union of Basic and Clinical Pharmacology. LXXX. The Class Frizzled Receptors. Pharmacol Rev. 62 (4): 632-67. [PMID:21079039] |
| Crystal structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. |
| Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC. (2010) Structures of the CXCR4 Chemokine GPCR with Small-Molecule and Cyclic Peptide Antagonists. Science. Published ahead of print Oct 7, 2010; DOI: 10.1126/science.1194396. [PMID:20929726] |
| Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. |
| Albizu L, Cottet M, Kralikova M, Stoev S, Seyer R, Brabet I, Roux T, Bazin H, Bourrier E, Lamarque L, Breton C, Rives ML, Newman A, Javitch J, Trinquet E, Manning M, Pin JP, Mouillac B, Durroux T. (2010) Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat Chem Biol. 6 (8): 587-94. [PMID:20622858] |
| IUPHAR review article published on the physiology, pharmacology and pathophysiological function of TRP channels. |
| Wu LJ, Sweet TB, Clapham DE. (2010) International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family. Pharmacol Rev. 62 (3): 381-404. [PMID:20716668] |
| Official IUPHAR nomenclature and review article published on the Apelin Receptor |
| Pitkin SL, Maguire JJ, Bonner TI, Davenport, AP. (2010) International Union of Basic and Clinical Pharmacology. LXXIV. Apelin Receptor Nomenclature, Distribution, Pharmacology, and Function. Pharmacol Rev. 62 (3): 331-42. [PMID:20605969] |
| Official IUPHAR nomenclature and review article published on Melatonin Receptors |
| Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. (2010) International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, Classification, and Pharmacology of G Protein-Coupled Melatonin Receptors. Pharmacol Rev. 62 (3): 343-80. [PMID:20605968] |
| 2009 |
| X-ray structure, symmetry and mechanism of an AMPA-subtype Glutamate Receptor |
|
Comments by J A. Peters, G.L. Collingridge, M. Spedding and R.W. Olsen: Ligand-gated ion channels (LGICs) exist as pentameric (i.e., nicotinic ACh, 5-HT3, GABAA and glycine), tetrameric (i.e., ionotropic glutamate) and trimeric (i.e., P2X) complexes. Although an almost complete medium resolution (4Å) structure of the nicotinic ACh receptor of Torpedo has been available for several years (1), it was only recently that a 3.1Å resolution crystal structure of a zebrafish P2X receptor was reported by the laboratory of Eric Gouaux (2). The same laboratory has now revealed in Nature (3) an almost complete 3.6Å resolution crystal structure of a representative of the third structural class of LGIC, the rat homotetrameric GluA2 receptor, in the closed state. The study confirms previous structures of the amino terminal domain (ATD) and ligand binding domain (LBD) obtained in isolation that is in each case arranged as a pair of dimers. Agonist/competitive antagonist binding sites are located within and not between subunits; this differs from the pentameric LGICs which have ligand binding sites at subunit interfaces (1). Remarkably, the new GluA2 receptor study reveals that crossover occurs between the ATD and LBD, such that subunit domains within the dimeric pairs swap. In addition, this structure allows a first glance of the ion channel, around which the subunits no longer exist in pairwise arrangement, but become independent and adopt a four-fold symmetry. The regions of the polypeptide linking the ATD to the LBD, and the latter to the transmembrane domains, are also revealed for the first time in this study, and will no doubt prove important for analyzing mechanisms both of agonist-gated channel opening and desensitization, as well as modulation by allosteric ligands. The laboratory of Eric Gouaux had previously reported the structural basis of desensitization (4) and of partial agonism (5) at the same receptors, and these reports were already of great interest for drug design, in this competitive area. This report is certain to initiate a flurry of experimental activity. |
|
(1) Unwin N. (2005). Refined structure of the nicotinic acetylcholine receptor at 4Å resolution. J Mol Biol. 346: 967-989. [PMID: 15701510] |
|
(2) Kawate T, Michel JC, Birdsong WT, Gouaux E. (2009). Crystal structure of the ATP-gated P2X4 ion channel in the closed state. Nature. 460: 592-598.[PMID: 19641588] |
|
(3) Sobolevsky AI, Rosconi MP, Gouaux E. (2009). X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor. Nature. 462: 745-756. [PMID: 19946266] |
|
(4) Jin R, Banke TG, Mayer ML, Traynelis SF, Gouaux E. (2003). Structural basis for partial agonist action at ionotropic glutamate receptors. Nat Neurosci. 6: 803-10. [PMID: 12872125] |
|
(5) Sun Y, Olson R, Horning M, Armstrong N, Mayer M, Gouaux E. (2002). Mechanism of glutamate receptor desensitization. Nature. 417: 245-53.[PMID: 12015593] |
| α2A-adrenergic receptor contributes to Type 2 diabetes |
| Comments by R.R. Neubig: Renström and colleagues report in Science Express that overexpression of the α2A-adrenergic receptor, which is encoded by a gene within a region of rat chromosome 1 (Niddm1) that influences susceptibility to diabetes, contributes to the reduced insulin secretion and impaired glucose tolerance in diabetic GK rats. The alpha2 adrenergic blocker yohimbine markedly improved insulin secretion and glucose handling in the diabetic rats. A similar effect was also shown in humans, where SNPs upstream of ADRA2A are associated with reduced glucose-stimulated plasma insulin levels and increased receptor mRNA in islets. This study suggests that in a subset of diabetics, alpha2 blockers that act selectively in periphery could represent a novel therapeutic approach. |
|
(1) Rosengren AH, Jokubka R, Tojjar D, Granhall C, Hansson O, Li DQ, Nagaraj V, Reinbothe TM, Tuncel J, Eliasson L, Groop L, Rorsman P, Salehi A, Lyssenko V, Luthman H, Renström E. (2010) Overexpression of Alpha2A-Adrenergic Receptors Contributes to Type 2 Diabetes. Science. 327 (5962): 217-20. [PMID: 19965390] |
| Official IUPHAR nomenclature and review article published on formyl peptide receptors |
| Ye RD, Boulay F, Wang JM, Dahlgren C, Gerard C, Parmentier M, Serhan CN, Murphy PM. (2009) International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol Rev. 61 (2): 119-61. [PMID:19498085] |
| Official IUPHAR nomenclature and review article published on trace amine receptor |
| Maguire JJ, Parker WA, Foord SM, Bonner TI, Neubig RR, Davenport AP. (2009) International Union of Pharmacology. LXXII. Recommendations for trace amine receptor nomenclature. Pharmacol Rev. 61 (1): 1-8. [PMID:19325074] |
| 2008 |
| Official IUPHAR nomenclature and review article published on free fatty acid receptors |
| Stoddart LA, Smith NJ, Milligan G. (2008) International Union of Pharmacology. LXXI. Free fatty acid receptors FFA1, -2, and -3: pharmacology and pathophysiological functions. Pharmacol Rev. 60 (4): 405-17. [PMID:19047536] |
| Revised recommendations for nomenclature of ligand-gated ion channels |
| The nomenclature of ligand-gated ion channels and their subunits has recently been re-examined by NC-IUPHAR. Their revised recommendations for nomenclature are summarised here. |
| Crystal Structure of a human A2A Adenosine Receptor |
| Comments by S.P.H. Alexander, T.I. Bonner and A. Christopoulos: Following on from reports of β-adrenoceptor structures reported recently, the 2.6 Å crystal structure of a further Gs-coupled receptor has been reported. The A2A receptor was modified, replacing the third intracellular loop with T4 bacteriophage lysozyme and deleting the C-terminus after the initial 25-30 residues beyond TM7. Purification in the presence of theophylline, which was later exchanged for the more selective A2A receptor antagonist ZM241385 allowed diffraction data to be obtained from the best 13 crystals. From the resulting solved structure, there were three main findings of particular note. The first is the presence of 4 disulfide bonds in the extracellular loop regions, which yields an organization that is very different from previously solved structures of rhodopsin and the β-adrenoceptor structures. Second, the transmembrane helices diverge from the orientations adopted by the corresponding domains in the rhodopsin and adrenoceptor structures. Finally, and perhaps most strikingly, these structural features result in a binding mode of the antagonist that places it in an extended conformation, almost perpendicular to the plane of the membrane, lined up against TM7 and interacting with the loop regions. This pose is very different to that predicted previously based on homology models. |
|
(1) Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC. (2008) The 2.6 Angstrom Crystal Structure of a Human A2A Adenosine Receptor Bound to an Antagonist. Science. Nov 21; 322 (5905): 1211-7. [PMID: 18832607] |
| Structure of the β1-adrenergic receptor |
| Comments by A.J. Harmar: Schertler and colleagues report the crystal structure of a β1-adrenergic receptor in complex with the antagonist cyanopindolol. Site directed mutagenesis was used to improve the thermostability of the protein and lock it in the antagonist state. This approach may be a fruitful one for determining the structures of other GPCRs. |
|
(1) Warne T, Serrano-Vega MJ , Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AGW, Tate CG, Schertler GFX. (2008) Structure of a beta1-adrenergic G-protein-coupled receptor. Nature. Jul 24; 454 (7203): 486-91 [PMID: 18594507] |
| 2007 |
| Crystal structure of human β2-adrenergic receptor |
| Comments by A.P.Davenport: To date, only 148 unique structures for membrane proteins have been determined, only 4 of these are human in origin and only one crystal structure of a GPCR has been solved, the visual sensory protein rhodopsin. Three papers in Science and Nature now report the structure of the human β2-adrenergic receptor. |
|
(1) Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK. (2007) Crystal structure of the human beta2 adrenergic G-protein-coupled receptor. Nature. Nov 15; 450 (7168): 383-7. [PMID: 17952055] |
|
(2) Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ,
Kuhn P, Weis WI, Kobilka BK, Stevens RC. (2007) High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor. Science. Nov 23; 318 (5854): 1258-65. [PMID: 17962520] |
| (3) Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK. (2007) GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function. Science. Nov 23; 318 (5854): 1266-73. [PMID: 17962519] |
Contact us | Print | Back to top | Help