Kapa opioidni receptor

Из Википедије, слободне енциклопедије
Kapa opioidni receptor 1
Identifikatori
Simboli OPRK1; KOR; OPRK
Vanjski ID OMIM165196 MGI97439 HomoloGene20253 IUPHAR: κ GeneCards: OPRK1 Gene
Pregled RNK izražavanja
PBB GE OPRK1 207553 at tn.png
podaci
Ortolozi
Vrsta Čovek Miš
Entrez 4986 18387
Ensembl ENSG00000082556 ENSMUSG00000025905
UniProt P41145 Q14AL5
RefSeq (mRNA) NM_000912 NM_011011
RefSeq (protein) NP_000903 NP_035141
Lokacija (UCSC) Chr 8:
54.3 - 54.33 Mb
Chr 1:
5.58 - 5.59 Mb
PubMed pretraga [1] [2]

κ-opioidni receptor (KOR) je tip opioidnog receptora koji vezuje opioidne peptide dinorfine kao primarne endogene ligande.[1] κ-opioidni receptor je široko rasprostranjen u mozgu (hipotalamus, centralna siva masa, i claustrum), kičmenoj moždini (substantia gelatinosa), i u neuronima bola.[2][3]

Tipovi[уреди]

Na osnovu istraživanja receptorskog vezivanja, tri varijante κ-opioidnog receptora se karakterisane: κ1, κ2, i κ3.[4][5] Međutim, samo jedan cDNK klon je identifikovan,[6] i stoga su ovi receptorski tipovi verovatno posledica interakcija sa drugum membranskim proteinima.[7]

Funkcija[уреди]

Dugo vremena je poznato da su agonisti κ-opioidnog receptora disforični.[8] Međutim, takođe je pokazano je da disforija uzrokovana agonistima κ-opioidnog receptora zavisna od pola osobe.[9][10] Nedavna istraživanja ukazuju na niz drugih nuspojava.[11] κ-opioidni receptor se smatra integralnom neurohemijskom komponentom adikcije i remisije.

Prenos signala[уреди]

Aktivacija κ-opioidnog receptora agonistima je vezana sa G proteinimam Gi/G0, koji naknadno povišavaju aktivnost fosfodiesteraze. Ona razlaže cAMP, proizvodeći inhibitorni efekat u neuronima.[12][13][14] κ-opioidni receptori se takođe sprežu sa unutrašnje ispravljajućim kalijumskim[15] i N-tip kalcijumskim jonskim kanalima.[16] Pokazano je da agonistom indukovana stimulacija κ-opioidnog receptora, poput drugih G-protein spregnutih receptora, može da dovede do aktivacije mitogenom-aktiviranih proteinskih kinaza (MAPK). To obuhvata ekstracelularnim signalom regulisanu kinazu, p38 MAP kinazu, i c-Jun N-terminalnu kinazu.[17][18][19][20][21][22]

Ligandi[уреди]

Sintetički alkaloid ketazocin[23] i terpenoidni prirodni proizvod salvinorin A[24] su potentni i selektivni agonisti κ-opioidnog receptora. Ovaj receptor takođe posreduje dejstvo halucinogenih nuspojava opioida poput pentazocina.[25]

Agonisti

Antagonisti

Prirodni agonist[уреди]

Menta[уреди]

Vista-xmag.png Za više informacija pogledajte mentol

Nađeno u brojnim vrstama minta (pepermint, Mentha spicata, i Mentha aquatica), prirodno jedinjenje mentol je slab agonist k-opioidnog receptora[29]. Mint isto tako može da desenzitiviše region putem aktivacije TRPM8 receptora ('hladnoća'/mentol receptor).[30]

Salvia divinorum[уреди]

Vista-xmag.png Za više informacija pogledajte Salvia divinorum

Ključno jedinjenje u Salvia divinorum, Salvinorin A, je poznato kao netoksični i potentni agonist κ-opioidnog receptora.[31][32]

Ibogain[уреди]

Vista-xmag.png Za više informacija pogledajte ibogain

Ibogain se koristi se za lečenje adikcije u pojedinim zemljama. On je postao ikona menadžmenta adikcije u nekim krugovima. Uprkos toga što ne izaziva zavisnost, ibogain se tretira kao kontrolisana supstanca u SAD-u, i stoga je njegovo posedovanje ilegalno. Ibogain je agonist κ-opioidnog receptora[33] i ta osobina može da doprinese njegovoj antizavisničkoj efikasnosti.

Interakcije[уреди]

Za κ-opioidni receptor je pokazano da interaguje sa natrijum-vodonik antiporter 3 regulatorom 1[34][35] i ubikvitinom C.[36]

Vidi još[уреди]

Референце[уреди]

  1. ^ James IF, Chavkin C, Goldstein A (1982). „Selectivity of dynorphin for kappa opioid receptors“. Life Sci. 31 (12-13): 1331-4. DOI:10.1016/0024-3205(82)90374-5. PMID 6128656. 
  2. ^ Fine, Perry G.; Russell K. Portenoy (2004). „Chapter 2: The Endogenous Opioid System“. A Clinical Guide to Opioid Analgesia. McGraw Hill. 
  3. ^ Mansour A, Fox CA, Akil H, Watson SJ (January 1995). „Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications“. Trends Neurosci. 18 (1): 22-9. DOI:10.1016/0166-2236(95)93946-U. PMID 7535487. 
  4. ^ de Costa BR, Rothman RB, Bykov V, Jacobson AE, Rice KC (February 1989). „Selective and enantiospecific acylation of kappa opioid receptors by (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexy l] benzeneacetamide. Demonstration of kappa receptor heterogeneity“. J. Med. Chem. 32 (2): 281-3. DOI:10.1021/jm00122a001. PMID 2536435. 
  5. ^ Rothman RB, France CP, Bykov V, De Costa BR, Jacobson AE, Woods JH, Rice KC (August 1989). „Pharmacological activities of optically pure enantiomers of the kappa opioid agonist, U50,488, and its cis diastereomer: evidence for three kappa receptor subtypes“. Eur. J. Pharmacol. 167 (3): 345-53. DOI:10.1016/0014-2999(89)90443-3. PMID 2553442. 
  6. ^ Mansson E, Bare L, Yang D (August 1994). „Isolation of a human kappa opioid receptor cDNA from placenta“. Biochem. Biophys. Res. Commun. 202 (3): 1431-7. DOI:10.1006/bbrc.1994.2091. PMID 8060324. 
  7. ^ Jordan BA, Devi LA (June 1999). „G-protein-coupled receptor heterodimerization modulates receptor function“. Nature 399 (6737): 697-700. DOI:10.1038/21441. PMID 10385123. 
  8. ^ Land BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (January 2008). „The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system“. J. Neurosci. 28 (2): 407-14. DOI:10.1523/JNEUROSCI.4458-07.2008. PMC 2612708. PMID 18184783. 
  9. ^ Lomas LM, Barrett AC, Terner JM, Lysle DT, Picker MJ (April 2007). „Sex differences in the potency of kappa opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats“. Psychopharmacology (Berl.) 191 (2): 273-85. DOI:10.1007/s00213-006-0663-1. PMID 17225166. 
  10. ^ Sershen H, Hashim A, Lajtha A (August 1998). „Gender differences in kappa-opioid modulation of cocaine-induced behavior and NMDA-evoked dopamine release“. Brain Res. 801 (1-2): 67-71. DOI:10.1016/S0006-8993(98)00546-0. PMID 9729284. 
  11. ^ Xuei X, Dick D, Flury-Wetherill L, Tian HJ, Agrawal A, Bierut L, Goate A, Bucholz K, Schuckit M, Nurnberger J, Tischfield J, Kuperman S, Porjesz B, Begleiter H, Foroud T, Edenberg HJ (November 2006). „Association of the kappa-opioid system with alcohol dependence“. Mol. Psychiatry 11 (11): 1016-24. DOI:10.1038/sj.mp.4001882. PMID 16924269. 
  12. ^ Lawrence DM, Bidlack JM (September 1993). „The kappa opioid receptor expressed on the mouse R1.1 thymoma cell line is coupled to adenylyl cyclase through a pertussis toxin-sensitive guanine nucleotide-binding regulatory protein“. J. Pharmacol. Exp. Ther. 266 (3): 1678-83. PMID 8103800. 
  13. ^ Konkoy CS, Childers SR (January 1993). „Relationship between kappa 1 opioid receptor binding and inhibition of adenylyl cyclase in guinea pig brain membranes“. Biochem. Pharmacol. 45 (1): 207-16. DOI:10.1016/0006-2952(93)90394-C. PMID 8381004. 
  14. ^ Schoffelmeer AN, Rice KC, Jacobson AE, et al. (September 1988). „Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate“. Eur. J. Pharmacol. 154 (2): 169-78. DOI:10.1016/0014-2999(88)90094-5. PMID 2906610. 
  15. ^ Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C (March 1995). „Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes“. Mol. Pharmacol. 47 (3): 551-7. PMID 7700253. 
  16. ^ Tallent M, Dichter MA, Bell GI, Reisine T (December 1994). „The cloned kappa opioid receptor couples to an N-type calcium current in undifferentiated PC-12 cells“. Neuroscience 63 (4): 1033-40. DOI:10.1016/0306-4522(94)90570-3. PMID 7700508. 
  17. ^ Bohn LM, Belcheva MM, Coscia CJ (February 2000). „Mitogenic signaling via endogenous kappa-opioid receptors in C6 glioma cells: evidence for the involvement of protein kinase C and the mitogen-activated protein kinase signaling cascade.“. J Neurochem 74 (2): 564-73. DOI:10.1046/j.1471-4159.2000.740564.x. PMC 2504523. PMID 10646507. 
  18. ^ Belcheva MM, Clark AL, Haas PD, Serna JS, Hahn JW, Kiss A, Coscia CJ (July 2005). „Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes“. J. Biol. Chem. 280 (30): 27662-9. DOI:10.1074/jbc.M502593200. PMC 1400585. PMID 15944153. 
  19. ^ Bruchas MR, Macey TA, Lowe JD, Chavkin C (June 2006). „Kappa opioid receptor activation of, pp. 38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes“. J. Biol. Chem. 281 (26): 18081-9. DOI:10.1074/jbc.M513640200. PMC 2096730. PMID 16648139. 
  20. ^ Bruchas MR, Xu M, Chavkin C (September 2008). „Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2“. Neuroreport 19 (14): 1417-22. DOI:10.1097/WNR.0b013e32830dd655. PMC 2641011. PMID 18766023. 
  21. ^ Kam AY, Chan AS, Wong YH (July 2004). „Kappa-opioid receptor signals through Src and focal adhesion kinase to stimulate c-Jun N-terminal kinases in transfected COS-7 cells and human monocytic THP-1 cells“. J. Pharmacol. Exp. Ther. 310 (1): 301-10. DOI:10.1124/jpet.104.065078. PMID 14996948. 
  22. ^ Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, Chavkin C (October 2007). „Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase“. J. Biol. Chem. 282 (41): 29803-11. DOI:10.1074/jbc.M705540200. PMC 2096775. PMID 17702750. 
  23. ^ Pasternak GW (June 1980). „Multiple opiate receptors: [3Hethylketocyclazocine receptor binding and ketocyclazocine analgesia“]. Proc. Natl. Acad. Sci. U.S.A. 77 (6): 3691-4. DOI:10.1073/pnas.77.6.3691. PMC 349684. PMID 6251477. 
  24. ^ Roth BL, Baner K, Westkaemper R, et al. (September 2002). „Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist“. Proc. Natl. Acad. Sci. U.S.A. 99 (18): 11934-9. DOI:10.1073/pnas.182234399. PMC 129372. PMID 12192085. 
  25. ^ Holtzman SG (February 1985). „Drug discrimination studies“. Drug Alcohol Depend 14 (3-4): 263-82. DOI:10.1016/0376-8716(85)90061-4. PMID 2859972. 
  26. ^ Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY (March 2008). „2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A“. The Journal of Pharmacology and Experimental Therapeutics 324 (3): 1073-83. DOI:10.1124/jpet.107.132142. PMC 2519046. PMID 18089845. 
  27. ^ Munro TA, Duncan KK, Xu W, Wang Y, Liu-Chen LY, Carlezon WA, Cohen BM, Béguin C (February 2008). „Standard protecting groups create potent and selective kappa opioids: salvinorin B alkoxymethyl ethers“. Bioorganic & Medicinal Chemistry 16 (3): 1279-86. DOI:10.1016/j.bmc.2007.10.067. PMC 2568987. PMID 17981041. 
  28. ^ Baker LE, Panos JJ, Killinger BA, Peet MM, Bell LM, Haliw LA, Walker SL (April 2009). „Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats“. Psychopharmacology 203 (2): 203-11. DOI:10.1007/s00213-008-1458-3. PMID 19153716. 
  29. ^ Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A, Ghelardini C (April 2002). „Menthol: a natural analgesic compound“. Neurosci. Lett. 322 (3): 145-8. DOI:10.1016/S0304-3940(01)02527-7. PMID 11897159. 
  30. ^ Werkheiser JL, Rawls SM, Cowan A (October 2006). „Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats“. Eur. J. Pharmacol. 547 (1-3): 101-5. DOI:10.1016/j.ejphar.2006.07.026. PMID 16945367. 
  31. ^ Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov V, Kreek MJ (January 2007). „Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans“. The Journal of pharmacology and experimental therapeutics 320 (1): 300-6. DOI:10.1124/jpet.106.112417. PMID 17060493. 
  32. ^ Chavkin C, Sud S, Jin W, Stewart J, Zjawiony JK, Siebert DJ, Toth BA, Hufeisen SJ, Roth BL (March 2004). „Salvinorin A, an active component of the hallucinogenic sage salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural and functional considerations“. The Journal of pharmacology and experimental therapeutics 308 (3): 1197-203. DOI:10.1124/jpet.103.059394. PMID 14718611. 
  33. ^ Glick SD, Maisonneuve IS (May 1998). „Mechanisms of antiaddictive actions of ibogaine“. Annals of the New York Academy of Sciences 844: 214-26. DOI:10.1111/j.1749-6632.1998.tb08237.x. PMID 9668680. 
  34. ^ Huang, Peng; Steplock Deborah, Weinman Edward J, Hall Randy A, Ding Zhe, Li Jianguo, Wang Yulin, Liu-Chen Lee-Yuan (Jun. 2004). „kappa Opioid receptor interacts with Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins“. J. Biol. Chem. (United States) 279 (24): 25002-9. DOI:10.1074/jbc.M313366200. ISSN 0021-9258. PMID 15070904. 
  35. ^ Li, Jian-Guo; Chen Chongguang, Liu-Chen Lee-Yuan (Jul. 2002). „Ezrin-radixin-moesin-binding phosphoprotein-50/Na+/H+ exchanger regulatory factor (EBP50/NHERF) blocks U50,488H-induced down-regulation of the human kappa opioid receptor by enhancing its recycling rate“. J. Biol. Chem. (United States) 277 (30): 27545-52. DOI:10.1074/jbc.M200058200. ISSN 0021-9258. PMID 12004055. 
  36. ^ Li, Jian-Guo; Haines Dale S, Liu-Chen Lee-Yuan (Apr. 2008). „Agonist-promoted Lys63-linked polyubiquitination of the human kappa-opioid receptor is involved in receptor down-regulation“. Mol. Pharmacol. (United States) 73 (4): 1319-30. DOI:10.1124/mol.107.042846. PMID 18212250. 

Литература[уреди]

Spoljašnje veze[уреди]