Tahikininski receptor 1

Tahikininski receptor 1
Identifikatori
Simboli	TACR1; SPR; NK1R; NKIR; TAC1R
Vanjski ID	OMIM: 162323 MGI: 98475 HomoloGene: 20288 IUPHAR: NK1 GeneCards: TACR1 Gene
Ontologija gena
Molekularna funkcija	• aktivnost rodopsinu-sličnog receptora; • receptorska aktivnost; • aktivnost tahikininskog receptora;
Celularna komponenta	• integralno sa ćelijskom membranom; • membrana;
Biološki proces	• inflamatorni respons; • prenos signala; • signalni put G-protein spregnutog receptora; • G-proteinska signalizacija, spregnuta sa IP3 sekundarnim glasnikom (aktivacija fosfolipaze C); • tahikininski signalni put; • mehano-senzorno ponašanje; • detekcija abiotičkog stimulusa; • respons na bol;
Pregled RNK izražavanja
	podaci
Ortolozi

edit

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

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

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

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

Agonisti

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

Antagonisti

Aprepitant
Kasopitant
Ezlopitant
Fosaprepitant
Lanepitant
Maropitant
Vestipitant
L-733,060
L-741,671
L-742,694
RP-67580 - potentan i selektivan antagonist, Ki 2.9nM, (3aR,7aR)-oktahidro-2-[1-imino-2-(2-metoksifenil)etil ]-7,7-difenil-4H-izoindol
RPR-100,893
CP-96345
CP-99994
GR-205,171
TAK-637
T-2328

Povezano

Literatura

↑ 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.
↑ ^2,0 ^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. Arhivirano iz originala na datum 2009-09-01. Pristupljeno 2014-05-08.
↑ ^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.
↑ ^4,0 ^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. Arhivirano iz originala na datum 2009-09-18. Pristupljeno 2014-05-08.
↑ ^5,0 ^5,1 Satake H., Kawada T. (August 2006). „Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors”. Current Drug Targets 7 (8): 963–974. DOI:10.2174/138945006778019273. Arhivirano iz originala na datum 2009-09-03. Pristupljeno 2014-05-08.
↑ ^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.
↑ 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.
↑ 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.
↑ 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.
↑ 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.
↑ 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

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

„Tachykinin Receptors: NK₁”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Arhivirano iz originala na datum 2011-05-16.
MeSH Receptors,+Neurokinin-1

[pmid1718267-1] 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.

[Ho_2004-2] 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. Arhivirano iz originala na datum 2009-09-01. Pristupljeno 2014-05-08.

[Page_2005-3] 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.

[Datar_2004-4] 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. Arhivirano iz originala na datum 2009-09-18. Pristupljeno 2014-05-08.

[Satake_2006-5] 5,0 ^5,1 Satake H., Kawada T. (August 2006). „Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors”. Current Drug Targets 7 (8): 963–974. DOI:10.2174/138945006778019273. Arhivirano iz originala na datum 2009-09-03. Pristupljeno 2014-05-08.

[Almeida_2004-6] 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.

[pmid12871173-7] 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.

[pmid19129399-8] 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.

[pmid18180429-9] 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.

[pmid18276852-10] 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.

[pmid16514255-11] 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.

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