IUPHAR DATABASE | HOT TOPICS

Hot Topics

The following are recent publications of interest.

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, GABA_A 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]

α_2A-adrenergic receptor contributes to Type 2 diabetes

Comments by R.R. Neubig:
Renström and colleagues report in Science Express that overexpression of the α_2A-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. (2009)
Overexpression of Alpha2A-Adrenergic Receptors Contributes to Type 2 Diabetes.
Science. Nov 19. [Epub ahead of print] [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]

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 A_2A 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 A_2A 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 A_2A 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 A_2A 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]

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]