إدارة الموسوعة 1: مراجعة واحدة

2013-11-01T17:54:21Z

مراجعة واحدة

صفحة جديدة

{{نهاية مسدودة|تاريخ=يونيو 2013}}

'''مستقبل التاخيكينين 1''' ('''TACR1''') المعروف أيضا باسم '''مستقبل 1 للتاخيكينين''' ('''NK1R''') أو '''مستقبل المادة ب''' ('''SPR''') هو عبارة عن مستقبل مزدوج بالبروتين ج الموجود في النظام العصبي المركزي والنظام العصبي المحيطي. كما أن الربيطة الداخلية لهذا المستقبل عبارة عن المادة ب على الرغم من أنه يوجد صلة بين التاخيكينينات الأخرى. ويتم إنتاج البروتين بواسطة جين ''TACR1''.
== الخصائص ==
تنتمي التاخيكينينات لعائلة النيوروببتيدات التي تشترك في نفس منطقة النهاية الكربونية الهيدروفوبي مع تسلسل الحمض الأميني ، حيث يمثل X الراسب الهيدروفوبي والذي يكون إما عطريًا أو أليفاتيًا متفرعًا من بيتا. وتختلف منطقة النهاية النِتْروجينِيَّة في الأنواع المختلفة للتاخيكينينات.‏<ref name = Ho_2004>{{Cite journal | last = Ho | first = W. Z. | last2 = Douglas | first2 = S. D. | title = Substance P and neurokinin-1 receptor modulation of HIV | journal = Journal of Neuroimmunology | volume = 157 | issue = 1&ndash;2 | pages = 48&ndash;55 | date = December 2004 |url= http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T03-4DP8JT6-2&_user=5915660&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=5915660&md5=3e140fa2944d54a39f08db8451ff9005=Citation | doi = 10.1016/j.jneuroim.2004.08.022 | pmid = 15579279 | postscript = {{inconsistent citations}}}}</ref><ref name = Page_2005>{{Cite journal | last = Page | first = N. M. | title = New challenges in the study of the mammalian Tachykinins | journal = Peptides | volume = 26 | issue = 8 | pages = 1356–1368 | date = August 2005 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T0M-4G0DDS8-4&_user=5915660&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000068853&_version=1&_urlVersion=0&_userid=5915660&md5=9523f37237e3a7147329fb4f28ffacec=Citation | doi = 10.1016/j.peptides.2005.03.030 | pmid = 16042976 | postscript = {{inconsistent citations}}}}</ref><ref name = Datar_2004>{{Cite journal | last = Datar | first = P. | last2 = Srivastava | first2 = S. | last3 = Coutinho | first3 = E. | last4 = Govil | first4 = G. | title = Substance P: Structure, Function, and Therapeutics | journal = Current Topics in Medicinal Chemistry | volume = 4 | issue = 1 | pages = 75–103 | year = 2004 | url = http://web.ebscohost.com/ehost/detail?vid=3&hid=14&sid=cbd0171a-72ef-47c3-bae2-063f39b1af3a%40sessionmgr2&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=12076762=Citation | doi = 10.2174/1568026043451636 | pmid = 14754378 | postscript = {{inconsistent citations}}}}</ref>؛ وتشير لفظة التاخيكينين إلى البداية السريعة للفعل الناتج عن الببتيدات الموجودة في العضلات الملساء. ؛ وتعد المادة ب أكثر عناصر عائلة التاخيكينين تداولاً وقوة. وتعتبر ببتيد مكون من 11 راسب حمض أميني وفقًا لتسلسل [[الحمض الأميني أَرْجينين‎ ‏Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met NH2‏.‏<ref name="Ho_2004"/>؛ وترتبط المادة ب مع كل ثلاثة من مستقبلات التاخيكينين ولكنها ترتبط بشكل أقوى مع مستقبل NK1‏.<ref name="Page_2005"/>؛

يتكون مستقبل التاخيكينين ‏NK‏1 <ref name = Satake_2006>{{Cite journal | last = Satake | first = H.‏ | last2 = Kawada | first2 = T‏. | title = Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors | journal = Current Drug Targets | volume = 7 | issue = 8 | pages = 963&ndash;974 | date = August 2006 | url = http://web.ebscohost.com/ehost/detail?vid=3&hid=8&sid=c900290b-e38a-4b8e-9dac-9f513104331b%40sessionmgr3&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=21848311=Citation | doi = 10.2174/138945006778019273 | postscript = {{inconsistent citations}}}}</ref> من 407 راسب حمض أميني، كما أن كتلة الجزيئية تساوي 58.000 .<ref name ="Ho_2004"/><ref name = Almeida_2004>{{Cite journal | last = Almeida | first = T. A. | last2 = Rojo | first2 = J. | last3 = Nieto | first3 = P. M. | last4 = Hernandez |first4 = M. | last5 = Martin | first5 = J. D. | last6 = Candenas | first6 = M. L. | title = Tachykinins and Tachykinins Receptors: Structure and Activity Relationships | journal = Current Medicinal Chemistry | volume = 11 | issue = 15 | pages = 2045–81 | date = August 2004 | url = http://web.ebscohost.com/ehost/detail?vid=3&hid=4&sid=4b46c517-3764-45fc-9dbd-1cb9d1cec680%40sessionmgr3&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=13996759=Citation | pmid = 15279567 | first4 = FM | last7 = Candenas | first7 = ML | postscript = {{inconsistent citations}}}}</ref> من مستقبل NK1 مثل بقية مستقبلات التاخيكينين الأخرى والتي تتكون من سبعة نطاقات عبر غشائية (TM) هيدروفوبية مع ثلاث عُرَى بَرَّانيّة وثلاث جَوَّانية ونهايات نِتْروجينِيَّة ونهايات كربونية هيولية. وتمتلك العرى مواقع وظيفية تتضمن الحمضين الأمينيين السيستئين المتعلقين بجِسْر ثُنائِيّ السُّلْفيد‎‎ ،حَمْضُ الأسبارتيك‎-Arg-Tyr، المسؤول عن الربط بين الأريستين و Lys/Arg-Lys/Arg -X-Lys/Arg، والذي يتفاعل مع البروتين ج.

=== التوزيع والوظيفة ===
يتواجد مستقبل NK1 في كلا الجهازين العصبي المركزي والعصبي المحيطي. ويظهر المستقبل في الخلايا العصبية وجذع الدماغ والخلايا الباطنية الوعائية والعضلات والأجهزة الهضمية والأجهزة التناسلية البولية والنسيج الرئوي والغدة الدرقية وأنواع مختلفة من خلايا الدم البيضاء.<ref name="Satake_2006"/><ref name = Saria_1999>{{Cite journal | last = Saria | first = A. | title = The Tachykinin NK1 receptor in the brain: pharmacology and putative functions | journal = European Journal of Pharmacology | volume = 375 | issue = 1&ndash;3 | pages = 51&ndash;60 | date = June 1999 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1J-3WXP063-5&_user=5915660&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000068853&_version=1&_urlVersion=0&_userid=5915660&md5=d6f447ad6a3e03bd50e933e605128c93=Citation | doi = 10.1016/S0014-2999(99)00259-9 | postscript = {{inconsistent citations}} | pmid=10443564}}</ref><ref name="Datar_2004"/><ref name="Almeida_2004"/>؛ وتتصل عملية الربط بين المادة ب والمستقبل NK1 بنقل إشارات الإجهاد والألم وتقلص العضلات الملساء والالتهاب.<ref name = Seto_2005>{{Cite journal | last = Seto | first = S. | last2 = Tanioka | first2 = A. | last3 = Ikeda | first3 = M. | last4 = Izawa | first4 = S. | title = Design and synthesis of novel 9-substituted-7-aryl-3,4,5,6-tetrahydro-2H-pyrido(4,3-b)- and (2,3-b)-1,5-oxazocin-6-ones as NK1 antagonists | journal = Bioorganic and Medicinal Chemistry Letters | volume = 15 | issue = 5 | pages = 1479&ndash;1484 | date = March 2005 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TF9-4FC3RRY-2&_user=5915660&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000068853&_version=1&_urlVersion=0&_userid=5915660&md5=50433f05a52a1184a13e6ecf3ecb9ff2=Citation | doi = 10.1016/j.bmcl.2004.12.091 | pmid = 15713411 | postscript = {{inconsistent citations}}}}</ref> وقد تم تجربة مضادات مستقبل NK1 في الصُّداع النِّصْفِيّ والقيء والأمراض العقلية. وفي الحقيقة، قد ثبتت فاعلية ابريببتانت (aprepitant) في العديد من نماذج الفيزيولوجية المرضية للقلق والاكتئاب.<ref name=Quartara_2006>{{Cite journal | last = Quartara | first = L. | last2 = Altamura | first2 = M. | title = Tachykinin receptors antagonists: From research to clinic | journal = Current Drug Targets | volume = 7 | issue = 8 | pages = 975–992 | date = August 2006 | url = http://web.ebscohost.com/ehost/detail?vid=3&hid=3&sid=1209dba9-203c-4bb0-990a-5cd3c9c841e7%40sessionmgr9&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=21848310=Citation | doi = 10.2174/138945006778019381 | pmid = 16918326 | postscript = {{inconsistent citations}}}}</ref> وكذلك بعض الأمراض التي يندرج فيها جهاز مستقبل NK1 مثل الربو والتهاب المفاصل الرثياني واضطرابات الجهاز الهضمي.<ref name = Humphrey__2003>{{Cite journal | last = Humphrey | first = J. M. | title = Medicinal Chemistry of Selective Neurokinin-1 Antagonists | journal = Current Topics in Medicinal Chemistry | volume = 3 | issue = 12 | pages = 1423&ndash;1435 | year = 2003 | url =http://web.ebscohost.com/ehost/detail?vid=4&hid=15&sid=c04bf2f1-4f7a-45ce-a30b-092df0686266%40sessionmgr9&bdata=JnNpdGU9ZWhvc3QtbGl2ZQ%3d%3d#db=aph&AN=11436699=Citation | doi = 10.2174/1568026033451925 | pmid=12871173 | postscript = {{inconsistent citations}}}}</ref>

=== Mechanism ===
SP is synthesized by neurons and transported to synaptic vesicles; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms.<ref name="Ho_2004"/>
When NK1 receptors are stimulated, they can generate various second messengers, which can trigger a wide range of effector mechanisms that regulate cellular excitability and function. One of those three well-defined, independent second messenger systems is stimulation, via phospholipase C, of phosphatidyl inositol, turnover leading to Ca mobilization from both intra- and extracellular sources. Second is the arachidonic acid mobilization via phospholipase A2 and third is the cAMP accumulation via stimulation of adenylate cyclase.<ref name=Quartara_1997>{{Cite journal | last = Quartara | first = L. | last2 = Maggi | first2 = C. A. | title = The tachykinin NK1 receptor. Part I: Ligands and mechanisms of cellular activation | journal = Neuropeptides | volume = 31 | issue = 6 | pages = 537&ndash;563 | date = December 1997 | url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WNR-4D2PDGX-99&_user=6149268&_coverDate=12%2F31%2F1997&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_version=1&_urlVersion=0&_userid=6149268&md5=69ab83979bd30d4d78e036b75ec0f871=Citation | doi = 10.1016/S0143-4179(97)90001-9 | postscript = {{inconsistent citations}} }}</ref> It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, is known to sensitize neutrophils and enhance dopamine release in the substantia nigra region in cat brain. From spinal neurons, SP is known to evoke release of neurotransmitters like acetylcholine, histamine and GABA. It is also known to secrete catecholamines and play a role in the regulation of blood pressure and hypertension. Likewise, SP is known to bind to N-methyl-D-aspartate (NMDA) receptors by eliciting excitation with calcium ion influx, which further releases nitric oxide. Studies in frogs have shown that SP elicits the release of prostaglandin E2 and prostacyclin by the arachidonic acid pathway, which leads to an increase in corticosteroid output.‏<ref name="Datar_2004"/>

In combination therapy, NK1 receptor antagonists appear to offer better control of delayed emesis and post-operative emesis than drug therapy without NK1 receptor antagonists. NK1 receptor antagonists block responses to a broader range of emetic stimuli than the established 5-HT3 antagonist treatments.‏<ref name="Humphrey__2003"/> وأفادت التقارير بأن مضادات مستقبلات NK1 المركزية مثل CP-99994، تمنع القيء المستحثة بآبومُورْفين‎ ولوبريميدين، حيث يؤثر المركبان على الآليات المركزية.<ref name="Saria_1999"/>

== الأهمية الإكلينيكية ==
ويعد هذا المستقبل هدف دوائي جذابًا، خاصةً في حالة استخدامه كمسكن قوي ومضاد للاكتئاب.<ref name="pmid12871173">{{cite journal | author = Humphrey JM | title = Medicinal chemistry of selective neurokinin-1 antagonists | journal = Current Topics in Medicinal Chemistry | volume = 3 | issue = 12 | pages = 1423–1435 | year = 2003 | pmid = 12871173 | doi = 10.2174/1568026033451925 }}</ref><ref name="pmid19129399">{{cite journal |author=Yu YJ, Arttamangkul S, Evans CJ, Williams JT, von Zastrow M |title=Neurokinin 1 receptors regulate morphine-induced endocytosis and desensitization of mu-opioid receptors in CNS neurons |journal=Journal of Neuroscience |volume=29 |issue=1 |pages=222–233 |year=2009 |month=January |pmid=19129399 |doi=10.1523/JNEUROSCI.4315-08.2009 |url= |pmc=2775560}}</ref> وفي عام 2008 قامت دراسة بتعيينه كأحد المرشحين لمسببات لاضطراب ثنائي القطب.<ref name="pmid18180429">{{cite journal | author = Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P | title = Family-based association study of lithium-related and other candidate genes in bipolar disorder | journal = Arch. Gen. Psychiatry | volume = 65 | issue = 1 | pages = 53–61 | year = 2008 | month = January | pmid = 18180429 | doi = 10.1001/archgenpsychiatry.2007.15 | url = }}</ref> وعلاوة على ذلك، فقد أعطت مضادات TACR1 الأمل في علاج إدمان المسكرات.<ref name="pmid18276852">{{cite journal | author = 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 | title = Neurokinin 1 receptor antagonism as a possible therapy for alcoholism | journal = Science | volume = 319 | issue = 5869 | pages = 1536–1539 | year = 2008 | month = March | pmid = 18276852 | doi = 10.1126/science.1153813 | url = }}</ref> وفي النهاية، فإنه يمكن أن يكون لمضادات TACR1 دور كمضاد للقيء جديد من نوعه.amp;lt;ref name="pmid16514255">{{cite journal | author = Jordan K | title = Neurokinin-1-receptor antagonists: a new approach in antiemetic therapy | journal = Onkologie | volume = 29 | issue = 1–2 | pages = 39–43 | year = 2006 | pmid = 16514255 | doi = 10.1159/000089800 }}</ref>

==لجينات منتقاة==
تتم إتاحة العديد من اللجينات المختارة لمستقبل NK1 حيث تمت تجربة العديد منها كمضاد للقيء في الاستخدامات الإكلينيكيّة.
{{refbegin|2}}

===المحرضات===
* GR-73632 - ناهضة قوية ومختارة, EC50 2nM, سلسلةعديدة الببتيد خماسية الحمض الأميني. CAS# 133156-06-6

===المضادات===
* أبريبيتانت
* كاسوبيتانت
* ايزلوبيتانت
* فوسابريبيتانت
* لينبيتانت
* ماروبيتانت
* فيستيبيتانت
* L-733,060
* L-741,671
* L-742,694
* RP-67580 - ناهضة قوية ومختارة, Ki 2.9nM, (3aR,7aR)-Octahydro-2-[1-imino-2-(2-methoxyphenyl)ethyl ]-7,7-diphenyl-4H-isoindol, CAS# 135911-02-3
* RPR-100,893
* CP-96345
* CP-99994
* GR-205,171
* TAK-637
* T-2328
{{refend}}

==انظر أيضًا==
* مضاد مستقبل NK1
* مستقبل التاخيكينين
* اكتشاف وتطوير مضادات مستقبل التاخيكينين 1

== المراجع ==
{{مراجع|2}}

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*{{cite journal | author=De Felipe C |title=Altered nociception, analgesia and aggression in mice lacking the receptor for substance P |journal=Nature |volume=392 |issue= 6674 |pages= 394–397 |year= 1998 |pmid= 9537323 |doi= 10.1038/32904 | author-separator=, | author2=Herrero JF | author3=O'Brien JA | display-authors=3 | last4=O'Brien | first4=John A. | last5=Palmer | first5=James A. | last6=Doyle | first6=Christopher A. | last7=Smith | first7=Andrew J. H. | last8=Laird | first8=Jennifer M. A. | last9=Belmonte | first9=Carlos }}

{{refend}}

==وصلات خارجية==
*{{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=3029 | title = Tachykinin Receptors: NK1 | accessdate = | author = | authorlink = | coauthors = | date = | format = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | language = | archiveurl = | archivedate = | quote = }}
* {{MeshName|Receptors,+Neurokinin-1}}

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مستقبل التاخيكينين 1 - تاريخ المراجعة

إدارة الموسوعة 1: مراجعة واحدة