Tahikininski receptor 1

Из Википедије, слободне енциклопедије
Tahikininski receptor 1
Identifikatori
Simboli TACR1; SPR; NK1R; NKIR; TAC1R
Vanjski ID OMIM162323 MGI98475 HomoloGene20288 IUPHAR: NK1 GeneCards: TACR1 Gene
Pregled RNK izražavanja
PBB GE TACR1 208049 s at tn.png
PBB GE TACR1 210637 at tn.png
podaci
Ortolozi
Vrsta Čovek Miš
Entrez 6869 21336
Ensembl ENSG00000115353 ENSMUSG00000030043
UniProt P25103 Q3V353
RefSeq (mRNA) NM_001058 NM_009313
RefSeq (protein) NP_001049 NP_033339
Lokacija (UCSC) Chr 2:
75.13 - 75.28 Mb
Chr 6:
82.37 - 82.53 Mb
PubMed pretraga [1] [2]

Tahikininski receptor 1 (TACR1, neurokininski 1 receptor, NK1R, ili receptor supstance P, SPR) je G protein spregnuti receptor koji je nađen u centralnom i perifernom nervnom sistemu. Endogeni ligand ovog receptora je supstanca P. On ima afinitet i za druge tahikinine. Protein je proizvod TACR1 gena.[1]

Osobine[уреди]

Tahikinini su familija neuropeptida koji imaju zajednički hidrofobni C-terminalni region sa aminokiselinskom sekvencom Phe-X-Gly-Leu-Met-NH2, gde X predstavlja hidrofobni ostatak koji je bilo aromatičan ili beta-razgranati alifatik. N-terminalni region varira između različitih tahikinina.[2][3][4] Termin tahikinin odražava brzi početak delovanja ovih peptida u glatkim mišićima.[4] SP je najistraženiji i najpotentniji član tahikininske familije. On je undekapeptid sa aminokiselinskom sekvencom Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2.[2] SP se vezuje za sva tri tahikininska receptora, ali se najjače vezuje za NK1 receptor.[3]

Tahikininski NK1 receptor[5] sadrži 407 aminokiselina, i ima molekulsku težinu od 58 kDa.[2][6] NK1 receptor, kao i drugi tahikininski receptori, sadrži sedam hidrofobnih transmembranskih domena sa tri ekstracelularne i tri intracelularne petlje, ekstracelularnim amino-terminusom i citoplazmatičnim karboksilnim-terminusom. Petlje sadrže funkcionalna mesta, koja obuhvataju dve cisteinske aminokiseline koje formiraju disulfidni most, Asp-Arg-Tyr motiv koji je odgovoran za vezivanje arestina, i Lys/Arg-Lys/Arg-X-X-Lys/Arg sekvencu koja interaguje sa G-proteinima.[5][6]

Klinički značaj[уреди]

Ovaj receptor se smatra atraktivnim ciljem za razvoj lekova sa analgetičkim i antidepresantskim svojstvima.[7][8] On je bio identifikovan kao kandidat u etiologiji manično-depresivne psihoze u jednoj studiji iz 2008.[9] Osim toga za TACR1 antagoniste je pokazano da potencijalno mogu da nađu primenu u lečenju alkoholizma.[10] Konačno, postoji mogućnost da se TACR1 antagonisti mogu koristiti kao antiemetike.[11]

Selektivni ligandi[уреди]

Mnogi selektivni NK1 ligandi za su dostupni, nekoliko njih je bilo u kliničkim ispitivanjima kao antiemetici.

Agonisti[уреди]

  • GR-73632 - potentan i selektivan agonist, EC50 2nM, polipeptid sa pet aminokiselina

Antagonisti[уреди]

Vidi još[уреди]

Literatura[уреди]

  1. Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE (1991). „Molecular cloning, structural characterization and functional expression of the human substance P receptor”. Biochem. Biophys. Res. Commun. 179 (3): 1232–40. DOI:10.1016/0006-291X(91)91704-G. PMID 1718267. 
  2. 2,0 2,1 2,2 Ho W. Z., Douglas S. D. (December 2004). „Substance P and neurokinin-1 receptor modulation of HIV”. Journal of Neuroimmunology 157 (1–2): 48–55. DOI:10.1016/j.jneuroim.2004.08.022. PMID 15579279. 
  3. 3,0 3,1 Page N. M. (August 2005). „New challenges in the study of the mammalian Tachykinins”. Peptides 26 (8): 1356–1368. DOI:10.1016/j.peptides.2005.03.030. PMID 16042976. 
  4. 4,0 4,1 Datar P., Srivastava S., Coutinho E., Govil G. (2004). „Substance P: Structure, Function, and Therapeutics”. Current Topics in Medicinal Chemistry 4 (1): 75–103. DOI:10.2174/1568026043451636. PMID 14754378. 
  5. 5,0 5,1 „Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors”. Current Drug Targets 7 (8): 963–974. August 2006. DOI:10.2174/138945006778019273. 
  6. 6,0 6,1 Almeida T. A., Rojo J., Nieto P. M., Hernandez M., Martin J. D., Candenas M. L. (August 2004). „Tachykinins and Tachykinins Receptors: Structure and Activity Relationships”. Current Medicinal Chemistry 11 (15): 2045–2081. PMID 15279567. 
  7. Humphrey JM (2003). „Medicinal chemistry of selective neurokinin-1 antagonists”. Current topics in medicinal chemistry 3 (12): 1423–35. DOI:10.2174/1568026033451925. PMID 12871173. 
  8. Yu YJ, Arttamangkul S, Evans CJ, Williams JT, von Zastrow M (January 2009). „Neurokinin 1 receptors regulate morphine-induced endocytosis and desensitization of mu-opioid receptors in CNS neurons”. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience 29 (1): 222–33. DOI:10.1523/JNEUROSCI.4315-08.2009. PMC 2775560. PMID 19129399. 
  9. Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P (January 2008). „Family-based association study of lithium-related and other candidate genes in bipolar disorder”. Arch. Gen. Psychiatry 65 (1): 53–61. DOI:10.1001/archgenpsychiatry.2007.15. PMID 18180429. 
  10. George DT, Gilman J, Hersh J, Thorsell A, Herion D, Geyer C, Peng X, Kielbasa W, Rawlings R, Brandt JE, Gehlert DR, Tauscher JT, Hunt SP, Hommer D, Heilig M (March 2008). „Neurokinin 1 receptor antagonism as a possible therapy for alcoholism”. Science (journal) 319 (5869): 1536–9. DOI:10.1126/science.1153813. PMID 18276852. 
  11. Jordan K (2006). „Neurokinin-1-receptor antagonists: a new approach in antiemetic therapy”. Onkologie 29 (1-2): 39–43. DOI:10.1159/000089800. PMID 16514255. 

Dodatna literatura[уреди]

  • Burcher E (1989). „The study of tachykinin receptors.”. Clin. Exp. Pharmacol. Physiol. 16 (6): 539–43. DOI:10.1111/j.1440-1681.1989.tb01602.x. PMID 2548782. 
  • Kowall NW, Quigley BJ, Krause JE, et al. (1993). „Substance P and substance P receptor histochemistry in human neurodegenerative diseases.”. Regul. Pept. 46 (1-2): 174–85. DOI:10.1016/0167-0115(93)90028-7. PMID 7692486. 
  • Patacchini R, Maggi CA (2002). „Peripheral tachykinin receptors as targets for new drugs.”. Eur. J. Pharmacol. 429 (1-3): 13–21. DOI:10.1016/S0014-2999(01)01301-2. PMID 11698023. 
  • Saito R, Takano Y, Kamiya HO (2003). „Roles of substance P and NK(1) receptor in the brainstem in the development of emesis.”. J. Pharmacol. Sci. 91 (2): 87–94. DOI:10.1254/jphs.91.87. PMID 12686752. 
  • Fong TM, Yu H, Huang RR, Strader CD (1992). „The extracellular domain of the neurokinin-1 receptor is required for high-affinity binding of peptides.”. Biochemistry 31 (47): 11806–11. DOI:10.1021/bi00162a019. PMID 1280161. 
  • Fong TM, Huang RR, Strader CD (1993). „Localization of agonist and antagonist binding domains of the human neurokinin-1 receptor.”. J. Biol. Chem. 267 (36): 25664–7. PMID 1281469. 
  • Fong TM, Anderson SA, Yu H, et al. (1992). „Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor.”. Mol. Pharmacol. 41 (1): 24–30. PMID 1310144. 
  • Takahashi K, Tanaka A, Hara M, Nakanishi S (1992). „The primary structure and gene organization of human substance P and neuromedin K receptors.”. Eur. J. Biochem. 204 (3): 1025–33. DOI:10.1111/j.1432-1033.1992.tb16724.x. PMID 1312928. 
  • Walsh DA, Mapp PI, Wharton J, et al. (1992). „Localisation and characterisation of substance P binding to human synovial tissue in rheumatoid arthritis.”. Ann. Rheum. Dis. 51 (3): 313–7. DOI:10.1136/ard.51.3.313. PMC 1004650. PMID 1374227. 
  • Gerard NP, Garraway LA, Eddy RL, et al. (1991). „Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones.”. Biochemistry 30 (44): 10640–6. DOI:10.1021/bi00108a006. PMID 1657150. 
  • Hopkins B, Powell SJ, Danks P, et al. (1991). „Isolation and characterisation of the human lung NK-1 receptor cDNA.”. Biochem. Biophys. Res. Commun. 180 (2): 1110–7. DOI:10.1016/S0006-291X(05)81181-7. PMID 1659396. 
  • Takeda Y, Chou KB, Takeda J, et al. (1991). „Molecular cloning, structural characterization and functional expression of the human substance P receptor.”. Biochem. Biophys. Res. Commun. 179 (3): 1232–40. DOI:10.1016/0006-291X(91)91704-G. PMID 1718267. 
  • Giuliani S, Barbanti G, Turini D, et al. (1992). „NK2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK2 receptor subtype.”. Eur. J. Pharmacol. 203 (3): 365–70. DOI:10.1016/0014-2999(91)90892-T. PMID 1723045. 
  • Ichinose H, Katoh S, Sueoka T, et al. (1991). „Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis.”. Biochem. Biophys. Res. Commun. 179 (1): 183–9. DOI:10.1016/0006-291X(91)91352-D. PMID 1883349. 
  • Thöny B, Heizmann CW, Mattei MG (1995). „Human GTP-cyclohydrolase I gene and sepiapterin reductase gene map to region 14q21-q22 and 2p14-p12, respectively, by in situ hybridization.”. Genomics 26 (1): 168–70. DOI:10.1016/0888-7543(95)80101-Q. PMID 7782081. 
  • Fong TM, Cascieri MA, Yu H, et al. (1993). „Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345.”. Nature 362 (6418): 350–3. DOI:10.1038/362350a0. PMID 8384323. 
  • Derocq JM, Ségui M, Blazy C, et al. (1997). „Effect of substance P on cytokine production by human astrocytic cells and blood mononuclear cells: characterization of novel tachykinin receptor antagonists.”. FEBS Lett. 399 (3): 321–5. DOI:10.1016/S0014-5793(96)01346-4. PMID 8985172. 
  • De Felipe C, Herrero JF, O'Brien JA, et al. (1998). „Altered nociception, analgesia and aggression in mice lacking the receptor for substance P.”. Nature 392 (6674): 394–7. DOI:10.1038/32904. PMID 9537323. 

Spoljašnje veze[уреди]