TRPV1

TRPV1
Identifikatori
Aliasi	TRPV1
Vanjski ID-jevi	OMIM: 602076 MGI: 1341787 HomoloGene: 12920 GeneCards: TRPV1
Lokacija gena (čovjek)
Hrom.	Hromosom 17 (čovjek)
Kraj	3,609,411 bp
Lokacija gena (miš)
Hrom.	Hromosom 11 (miš)
Kraj	73,152,068 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• nucleotide binding; • ion channel activity; • phosphoprotein binding; • ATP binding; • cation transmembrane transporter activity; • cation channel activity; • ligand-gated ion channel activity; • calcium-release channel activity; • temperature-gated ion channel activity; • vezivanje identičnih proteina; • chloride channel regulator activity; • transmembrane signaling receptor activity; • excitatory extracellular ligand-gated ion channel activity; • calcium channel activity; • extracellular ligand-gated ion channel activity; • phosphatidylinositol binding; • vezivanje iona metala; • calmodulin binding; • GO:0001948, GO:0016582 vezivanje za proteine;
Ćelijska komponenta	• integral component of membrane; • postsynaptic membrane; • projekcija ćelije; • membrana; • ćelijska membrana; • sinapsa; • međućelijske veze; • dendritic spine membrane; • citosol; • neuronal cell body; • intrinsic component of plasma membrane; • dendrit; • external side of plasma membrane; • neuron projection; • integral component of plasma membrane; • mitohondrija;
Biološki proces	• ion transport; • chemosensory behavior; • cell surface receptor signaling pathway; • calcium ion transmembrane transport; • thermoception; • calcium ion transport; • inflammatory response; • transmembrane transport; • release of sequestered calcium ion into cytosol; • GO:1901227 negative regulation of transcription by RNA polymerase II; • diet induced thermogenesis; • detection of chemical stimulus involved in sensory perception of pain; • microglial cell activation; • cellular response to growth factor stimulus; • positive regulation of gastric acid secretion; • response to peptide hormone; • cellular response to nerve growth factor stimulus; • positive regulation of nitric oxide biosynthetic process; • negative regulation of establishment of blood-brain barrier; • lipid metabolism; • temperature homeostasis; • response to heat; • cellular response to temperature stimulus; • positive regulation of cytosolic calcium ion concentration; • peptide secretion; • detection of temperature stimulus involved in sensory perception of pain; • sensory perception of mechanical stimulus; • smooth muscle contraction involved in micturition; • behavioral response to pain; • response to pain; • cellular response to alkaloid; • cellular response to cytokine stimulus; • fever generation; • detection of temperature stimulus involved in thermoception; • positive regulation of apoptotic process; • urinary bladder smooth muscle contraction; • glutamate secretion; • Nocicepcija; • cellular response to tumor necrosis factor; • cellular response to ATP; • ion transmembrane transport; • response to pH; • response to organonitrogen compound; • cellular response to heat; • protein homotetramerization; • excitatory postsynaptic potential; • cellular response to acidic pH; • response to capsazepine; • calcium ion import across plasma membrane; • negative regulation of systemic arterial blood pressure; • negative regulation of heart rate; • negative regulation of mitochondrial membrane potential;
	Izvori:Amigo / QuickGO
Ortolozi
	7442
	193034
	ENSG00000196689
	ENSMUSG00000005952
	Q8NER1
	Q704Y3
	NM_018727; NM_080704; NM_080705; NM_080706
	NM_001001445
	NP_061197; NP_542435; NP_542436; NP_542437
	NP_001001445
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Član 1 podporodice V prolaznog recepcijskog potencijala kationskog kanala (TrpV1), poznat i kao kapsaicinski receptor i vaniloidni receptor 1, je protein koji je kod ljudi kodiran genom TRPV1. To je bio prvi izolirani član prolaznih receptora potencijalnih proteinskih vaniloidnih receptora, koji su pak potporodica potencijalne proteinske skupine prolaznih receptora.^[5]^[6] Ovaj protein je član grupe TRPV, privremenih potencijalnih receptora porodice ionskih kanala.^[7]

Funkcija TRPV1 je otkrivanje i regulacija tjelesne temperature. Pored toga, TRPV1 pruža upareni osjećaj vrućine i bola (nocicepcija). U primarnom aferentnom senzornim neuronima, sarađuje sa TRPA1 ^[8]^[9] (hemijski iritantni receptor) da posreduje u otkrivanju štetnih podražaja iz okoline.^[10]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 839 aminokiselina, a molekulska težina 94.956 Da.^[11]

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

10	20	30	40	50
MKKWSSTDLG	AAADPLQKDT	CPDPLDGDPN	SRPPPAKPQL	STAKSRTRLF
GKGDSEEAFP	VDCPHEEGEL	DSCPTITVSP	VITIQRPGDG	PTGARLLSQD
SVAASTEKTL	RLYDRRSIFE	AVAQNNCQDL	ESLLLFLQKS	KKHLTDNEFK
DPETGKTCLL	KAMLNLHDGQ	NTTIPLLLEI	ARQTDSLKEL	VNASYTDSYY
KGQTALHIAI	ERRNMALVTL	LVENGADVQA	AAHGDFFKKT	KGRPGFYFGE
LPLSLAACTN	QLGIVKFLLQ	NSWQTADISA	RDSVGNTVLH	ALVEVADNTA
DNTKFVTSMY	NEILMLGAKL	HPTLKLEELT	NKKGMTPLAL	AAGTGKIGVL
AYILQREIQE	PECRHLSRKF	TEWAYGPVHS	SLYDLSCIDT	CEKNSVLEVI
AYSSSETPNR	HDMLLVEPLN	RLLQDKWDRF	VKRIFYFNFL	VYCLYMIIFT
MAAYYRPVDG	LPPFKMEKTG	DYFRVTGEIL	SVLGGVYFFF	RGIQYFLQRR
PSMKTLFVDS	YSEMLFFLQS	LFMLATVVLY	FSHLKEYVAS	MVFSLALGWT
NMLYYTRGFQ	QMGIYAVMIE	KMILRDLCRF	MFVYIVFLFG	FSTAVVTLIE
DGKNDSLPSE	STSHRWRGPA	CRPPDSSYNS	LYSTCLELFK	FTIGMGDLEF
TENYDFKAVF	IILLLAYVIL	TYILLLNMLI	ALMGETVNKI	AQESKNIWKL
QRAITILDTE	KSFLKCMRKA	FRSGKLLQVG	YTPDGKDDYR	WCFRVDEVNW
TTWNTNVGII	NEDPGNCEGV	KRTLSFSLRS	SRVSGRHWKN	FALVPLLREA
SARDRQSAQP	EEVYLRQFSG	SLKPEDAEVF	KSPAASGEK

Funkcija uredi

TRPV1 je neselektivni kationski kanal koji se može aktivirati širokim spektrom egzogenih i endogennih fizičkih i hemijskih podražaja. Najpoznatiji aktivatori TRPV1 su: temperatura viša od 4 °C, kiseli uslovi, kapsaicin (nadražujući spoj u ljutoj čili papričici) i alil-izotiocijanat, oštar spoj u senfu i vasabiju.^[12] Aktivacija TRPV1 dovodi do bolnog peckanja. Njegovi endogeni aktivatori uključuju: nizak pH (kiseli uslovi), endokanabinoid anandamid, N-oleil-dopamin i N-arahidonoil-dopamin. TRPV1 receptori se uglavnom nalaze u nociceptivnim neuronima perifernog nervnog sistema, ali su također opisani u mnogim drugim tkivima, uključujući centralni nervni sistem. TRPV1 je uključen u prenos i modulaciju bola (nocicepcija), kao i integraciju različitih bolnih podražaja^[13]^[14]

Senzibilizacija uredi

Osetljivost TRPV1 na štetne stimuluse, kao što su visoke temperature, nije statična. Nakon oštećenja tkiva i posljedičnih upala, oslobađa se niz medijatora upale, kao što su različiti prostaglandini i bradikinini. Ova sredstva povećavaju osjetljivost nociceptora na štetne podražaje. To se manifestuje kao povećana osjetljivost na bolne podražaje (hiperalgezija) ili osjećaj bola kao odgovor na nebolne podražaje (alodinija). Većina senzibilizirajućih proupalnih sredstava aktiviraju put fosfolipaze C. Pokazalo se da fosforilacija TRPV1 pomoću protein-kinaza C ima ulogu u senzibilizaciji TRPV1. Cijepanje PIP2 pomoću PLC-beta može rezultirati dezinhibicijom TRPV1 i, kao posljedica toga, doprinijeti osjetljivosti TRPV1 na štetne stimuluse.

Desenzibilizacija uredi

Nakon dužeg izlaganja kapsaicinu, aktivnost TRPV1 se smanjuje, fenomen zvani desenzibilizacija . Vanćelijski kalcijevi ioni su potrebni za ovaj fenomen, pa priliv kalcija i posljedično povećanje unutarćelijskog kalcija posreduju u ovom efektu. Razni signalni putevi, kao što su kalmodulinski i kalcineurinski, te smanjenje PIP₂, uključeni su u desenzibilizaciju TRPV1. Smatra se da desenzibilizacija TRPV1 leži u osnovi paradoksalnog analgetskog efekta kapsaicina.

Klinički značaj uredi

Periferni nervni sistem uredi

Kao rezultat svog uključivanja u nocicepciju, TRPV1 je bio meta za razvoj lijekova za smanjenje bolova (analgetici). Korištene su tri glavne strategije:

Upotreba TRPV1 uredi

TRPV1 receptor je koristan za mjerenje kako organizam može osjetiti promjenu temperature. U laboratoriji se receptor može ukloniti iz miševa, što im onemogućava da otkriju razlike u temperaturi okoline. U farmaceutskom polju to omogućava blokiranje receptora toplote, pružajući pacijentima s upalnim poremećajima ili jakom peckajućom boli da se izliječe bez bolova. Nedostatak TRPV1 receptora daje uvid u razvoj mozga, jer u dovoljnoj dozi toplota može ubiti većinu organizama, pa ovaj postupak uklanjanja pokazuje istraživačima kako nemogućnost osjećanja topline može biti štetna za preživljavanje organizma, a zatim to prevesti na poremećaje ljudske toplote.

Antagonisti uredi

Antagonisti blokiraju aktivnost TRPV1, smanjujući tako bol. Identificirani antagonisti uključuju kompetitivni antagonist kapsazepina i nekonkurentni antagonist crvenog rutenija. Ova sredstva mogu biti korisna kada se sistemski primjenjuju.^[15] Brojne antagoniste TRPV1 razvile su farmaceutske kompanije. TRPV1 antagonisti pokazali su efikasnost u smanjenju nocicepcije od upalnih i neuropatskih bolova kod pacovskih modela.^[16] Ovo pruža dokaz da je TRPV1 jedini receptor kapsaicina.^[17]

Kod ljudi, lijekovi koji djeluju na TRPV1 receptore mogu se koristiti za liječenje neuropatskog bola povezanog sa multiplom sklerozom, hemoterapijama ili amputacijaama, kao i bolova povezanih s upalnim odgovorom oštećenog tkiva, kao što je osteoartritis.^[18]

Ovi lijekovi mogu uticati na tjelesnu temperaturu (hipertermija), što je izazov za terapijsku primjenu. Naprimjer, privremeni porast temperature (~1 °C u trajanju od približno 40 minuta, vrativši se na početnu liniju za 40 minuta) izmjeren je kod pacova primjenom antagonista TRPV1 AMG-9810.^[19] Uloga TRPV1 u regulaciji tjelesne temperature pojavila se kao tema posljednjih nekoliko godina. Na osnovu niza TRPV-selektivnih antagonista koji uzrokuju blago povišenje tjelesne temperature (hipertermija), predloženo je da je TRPV1 tonusno aktivan " in vivo " i regulira tjelesnu temperature, signalizirajući tijelu da se "ohladi". Bez ovih signala, tijelo se pregrijava. Slično tome, ovo objašnjava sklonost kapsaicina (agonista TRPV1) da izazove znojenje (tj. signal za smanjenje tjelesne temperature). U nedavnom izvještaju utvrđeno je da su tonusno aktivni TRPV1 kanali prisutni u unutrašnjosti i zadržavaju trajni supresivni efekt na tjelesnu temperaturu.^[20] Recently, it was proposed that predominant function of TRPV1 is body temperature maintenance.^[21] Eksperimenti su pokazali da blokada TRPV1 povećava tjelesnu temperaturu kod više vrsta, uključujući glodare i ljude, sugerirajući da je TRPV1 uključen u održavanje tjelesne temperature. U 2008., za AMG-517, izuzetno selektivnog antagonistu TRPV1 odustalo se od kliničkih ispitivanja zbog uzroka hipertermije (~ 38,3 °C srednje povišenje koje je bilo najintenzivnije 1. dana, ali je oslabljeno od 2–7. dana).^[22] Još jedna molekula, SB-705498, također je klinički ispitivana, ali njen učinak na tjelesnu temperaturu nije zabilježen.^[23]^[24] Kako se povećavamo razumijevanje agonizma TRPV1 specifičnog za modalitete, čini se da terapije sljedeće generacije koje ciljaju TRPV1 imaju potencijal za hipertermiju u sporednom koraku.^[25] Šta više, za najmanje dvije indikacije ili pristupa ovo može biti sekundarno pitanje. Tamo gdje je terapijski pristup (npr. u analgeziji) desenzibilizacija posredovana agonistima, tada hipertermijski efekti djelovanja antagonista možda neće biti relevantni. Sekundarno, u aplikacijama kao što je antagonizam TRPV1 za liječenje teških stanja, kao što je srčana insuficijencija, tada može doći do prihvatljivog kompromisa s blagom hipertermijom, iako nije primijećena hipertermija na glodarskim modelima srčane insuficijencije liječenim BCTC, SB- 366791 ili AMG-9810.^[26]^[27]Posttranslacijska modifikacija TRPV1 proteina njegovim fosforilacijom je kritična za njegovu funkcionalnost. Izvještaji objavljeni iz NIH sugeriraju da je fosforilacija TRPV1 posredovana Cdk5-om potrebna za njegovo otvaranje kanala izazvanog ligandom.^[28]

Centralni nervni sistem uredi

TRPV1 je također izražen na visokim nivoima u centralnom nervnom sistemu i predložen je kao meta za liječenje ne samo bolova, već i drugih stanja kao što je anksioznost.^[29] Nadalje, čini se da TRPV1 posreduje u dugotrajnoj sinapsnoj depresiji (LTD) u hipokampusu.^[30] LTD je povezan sa smanjenjem sposobnosti stvaranja novih utisaka, za razliku od njegove suprotnosti dugoročno potenciranje (LTP), koja pomaže u formiranju memorije. Dinamični obrazac LTD i LTP, koji se javlja u mnogim sinapsama pruževog kôda za formiranje memorije. Dugotrajna depresija i naknadno ograničavanje sinapsi sa smanjenom aktivnošću važan je aspekt formiranja memorije. Na presjecima mozga pacova, uočeno je da aktivacija TRPV1 toplinom ili induciranim kapsaicinom LTD, dok je kapsazepin blokirao sposobnost kapsaicina da inducira LTD. U moždanom stablu (jezgro solitarnog trakta), TRPV1 kontrolira asinhrono i spontano oslobađanje glutamata od nemijeliniziranih kranijalnih utrobnih aferenata – procesi oslobađanja koji su aktivni pri normalnim temperaturama i stoga se prilično razlikuju od TRPV1-ih odgovora u bolnoj vrućini.^[31] Stoga može postojati terapijski potencijal za modulaciju TRPV1 u centralnom nervnom sistemu, možda kao tretman epilepsije (TRPV1 je već meta u perifernom nervnom sistemu za ublažavanje bolova).

Interakcije uredi

Pokazano je da TRPV1 ima interakcije sa:

Otkriće uredi

Poznato je da neuroni korijena leđne ganglije (DRG) sisara izražavaju toplotno osetljiv ionski kanal, koji se može aktivirati kapsaicinom.^[35] Stoga je istraživačka grupa Davida Juliusa stvorila biblioteku cDNK gena, eksprimiranih u neuronima korijena leđnih ganglija I eksprimirala u ćelijama klonova HEK 293 | HEK 293 i tražila ćelije koje reaguju na kapsaicin prilivom kalcija (koji HEK -293 obično nema). Nakon nekoliko rundi pregleda i podjele biblioteke, jedan klon koji kodirao TRPV1 i kanal je konačno identificiran 1997. To je prvi identificirani TRPV kanal.^[5]

Također pogledajte uredi

Reference uredi

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000196689 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000005952 - Ensembl, maj 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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^ Peters JH, McDougall SJ, Fawley JA, Smith SM, Andresen MC (mart 2010). "Primary afferent activation of thermosensitive TRPV1 triggers asynchronous glutamate release at central neurons". Neuron. 65 (5): 657–69. doi:10.1016/j.neuron.2010.02.017. PMC 2837850. PMID 20223201.
^ Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M (juni 2003). "Structural determinant of TRPV1 desensitization interacts with calmodulin". Proceedings of the National Academy of Sciences of the United States of America. 100 (13): 8002–6. Bibcode:2003PNAS..100.8002N. doi:10.1073/pnas.1337252100. PMC 164702. PMID 12808128.
^ ^a ^b Morenilla-Palao C, Planells-Cases R, García-Sanz N, Ferrer-Montiel A (juni 2004). "Regulated exocytosis contributes to protein kinase C potentiation of vanilloid receptor activity". The Journal of Biological Chemistry. 279 (24): 25665–72. doi:10.1074/jbc.M311515200. PMID 15066994.
^ ^a ^b Fonseca BM, Correia-da-Silva G, Teixeira NA (maj 2018). "Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis". Journal of Physiology and Biochemistry. 74 (2): 261–272. doi:10.1007/s13105-018-0611-7. PMID 29441458. S2CID 25294779.
^ Heyman I, Rang HP (maj 1985). "Depolarizing responses to capsaicin in a subpopulation of rat dorsal root ganglion cells". Neuroscience Letters. 56 (1): 69–75. doi:10.1016/0304-3940(85)90442-2. PMID 4011050. S2CID 42235338.

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Vanjski linkovi uredi

Vanilloid receptors na US National Library of Medicine Medical Subject Headings (MeSH)
O35433

Šablon:Modulatori potencijalnih kanala privremenog receptora

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000196689 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000005952 - Ensembl, maj 2017

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[pmid12808128-32] Numazaki M, Tominaga T, Takeuchi K, Murayama N, Toyooka H, Tominaga M (juni 2003). "Structural determinant of TRPV1 desensitization interacts with calmodulin". Proceedings of the National Academy of Sciences of the United States of America. 100 (13): 8002–6. Bibcode:2003PNAS..100.8002N. doi:10.1073/pnas.1337252100. PMC 164702. PMID 12808128.

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[:0-34] Fonseca BM, Correia-da-Silva G, Teixeira NA (maj 2018). "Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis". Journal of Physiology and Biochemistry. 74 (2): 261–272. doi:10.1007/s13105-018-0611-7. PMID 29441458. S2CID 25294779.

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