Adenosine receptors
Adenosine receptors , also called A receptors , P 1 purinoceptors or P 1 receptors , are receptors that are activated by the purine nucleoside adenosine . The four currently known representatives of this group of purinoceptors , designated A 1 , A 2A , A 2B and A 3 , play in the central nervous system as well as in the regulation of cardiovascular functions and immune responsesa role. These effects are triggered by a receptor-mediated activation of G proteins . The effects of the xanthines caffeine , theophylline and theobromine can at least in part be explained by an interaction with adenosine receptors. In animal models and clinical studies, it has been shown that A 2A receptor antagonists, together with the intake of levodopa or D 2 receptor agonists, can amplify the therapeutic effects of these. The A 2A receptor antagonist istradefylline is used to treat Parkinson's disease . With regadenoson 2008, the first A was in the United States 2A agonist approved for the treatment. Other antagonists and agonists are currently being developed as potential drugs .
| A 1 | A 2A | A 2B | A 3 | |
|---|---|---|---|---|
| genetics | ||||
| Gene name | ADORA1 | ADORA2A | ADORA2B | ADORA3 |
| Gene locus | 1q32.1 | 22q11.23 | 17p12-p11.2 | 1p21-p13 |
| protein | ||||
| UniProt-Bez. | P30542 | P29274 | P29275 | P33765 |
| structure | 7TM | 7TM | 7TM | 7TM |
| length | 326 amino acids | 412 amino acids | 332 amino acids | 318 amino acids |
| pharmacology | ||||
| Signal transduction | G i / o | G s | G s | G i / o |
| function | negative inotropy and chronotropy |
Pain inhibition of platelet aggregation vasodilation |
Release of inflammatory mediators | Mast cell degranulation |
| Agonists | Adenosine N 6 -cyclopentyladenosine |
Adenosine regadenoson CGS-21680 2- (1- ( E ) -hexenyl) adenosine-5'- N -ethyluronamide (HENECA) ATL-146e |
Adenosine BAY 60-6583 |
Adenosine CP-532,903 CF-101 (IB-MECA) 2-Cl-IB-MECA |
| Antagonists |
Caffeine Theophylline 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX) |
Caffeine Theophyllin Istradefyllin ZM 241385 SCH 58261 |
Theophylline MRS 1753 MRS 1706 PSB 1115 |
Theophylline VUF 5574 MRS 1220 MRS 1523 MRS 1191 |
history
Alan Drury and Albert von Szent-Györgyi Nagyrápolt discovered in 1929 that adenosine can influence various body functions. These effects were originally attributed to transport proteins and intracellular processes. Contrary to this hypothesis, L. Bruce Cobbin postulated in 1974 that specific receptors were responsible for these effects. It was proven in the late 1970s that the adenosine receptor is not just a single receptor, but that several isoforms exist. In the search for new G-protein-coupled receptors, the first adenosine receptors, the A 1 and A 2A receptors, were cloned by chance at the end of the 1980s . The three-dimensional structure of an adenosine receptor, the A 2A receptor, was able to be elucidated in 2008 as a fusion protein with the help of X-ray structure analysis. This makes this receptor one of the first G protein-coupled receptors for which detailed information about its spatial structure is available.
Individual evidence
- ^ Micaela Morelli, Fabio Blandini, Nicola Simola, Robert A. Hauser: A2AReceptor Antagonism and Dyskinesia in Parkinson's Disease . In: Parkinson's Disease . tape 2012 , 2012, p. 1–8 , doi : 10.1155 / 2012/489853 , PMID 22754707 , PMC 3382949 (free full text).
- ^ Marie Therese Armentero, Annalisa Pinna, Sergi Ferré, José Luis Lanciego, Christa E. Müller: Past, present and future of A2A adenosine receptor antagonists in the therapy of Parkinson's disease . In: Pharmacology & Therapeutics . tape 132 , no. 3 , December 2011, p. 280–299 , doi : 10.1016 / j.pharmthera.2011.07.004 , PMID 21810444 , PMC 3205226 (free full text).
- ↑ Reuters: CV Therapeutics and Astellas Announce FDA Approval for Lexiscan (TM) (regadenoson) Injection. (en, PDF; 23kB)
- ↑ Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J: International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors . In: Pharmacol Rev . 53, No. 4, 2001, pp. 527-52. PMID 11734617 .
- ^ AN Drury, A. Szent-György: The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart . In: The Journal of Physiology . tape 68 , no. 3 , 1929, pp. 213-237 , doi : 10.1113 / jphysiol.1929.sp002608 , PMID 16994064 , PMC 1402863 (free full text).
- ^ Cobbin LB, Einstein R, Maguire MH: Studies on the coronary dilator actions of some adenosine analogues . In: Br J Pharmacol . 50, No. 1, January 1974, pp. 25-33. PMID 4362949 . PMC 1776578 (free full text).
- ^ Van Calker D, Müller M, Hamprecht B: Adenosine regulates via two different types of receptors, the accumulation of cyclic AMP in cultured brain cells . In: J. Neurochem. . 33, No. 5, November 1979, pp. 999-1005. PMID 228008 .
- ^ Londos C, Cooper DM, Wolff J: Subclasses of external adenosine receptors . In: Proc. Natl. Acad. Sci. USA . 77, No. 5, May 1980, pp. 2551-2554. PMID 6248853 . PMC 349439 (free full text).
- ↑ Libert F, Parmentier M, Lefort A, et al. : Selective amplification and cloning of four new members of the G protein-coupled receptor family . In: Science . 244, No. 4904, May 1989, pp. 569-572. PMID 2541503 .
- ↑ Jaakola VP, Griffith MT, Hanson MA, et al. : The 2.6 angstrom crystal structure of a human A2A adenosine receptor bound to an antagonist . In: Science . 322, No. 5905, November 2008, pp. 1211-1217. doi : 10.1126 / science.1164772 . PMID 18832607 . PMC 2586971 (free full text).
- ↑ Xu F, Wu H, Katritch V, et al. : Structure of an agonist-bound human A2A adenosine receptor . In: Science . 332, No. 6027, 2011, pp. 322-327. doi : 10.1126 / science.1202793 . PMID 21393508 . PMC 3086811 (free full text).
- ↑ Lebon G, Warne T, Edwards PC, et al. : Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation . In: Nature . 474, No. 7352, 2011, pp. 521-525. doi : 10.1038 / nature10136 . PMID 21593763 . PMC 3146096 (free full text).