World Library  
Flag as Inappropriate
Email this Article

Tachykinin receptor 1

Article Id: WHEBN0012412341
Reproduction Date:

Title: Tachykinin receptor 1  
Author: World Heritage Encyclopedia
Language: English
Subject: Obsessive–compulsive disorder, Arginine vasopressin receptor 1A, Obsessional jealousy, OCD Action, Adam S. Radomsky
Publisher: World Heritage Encyclopedia

Tachykinin receptor 1

Tachykinin receptor 1

Rendering based on PDB .
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; NK1R; NKIR; SPR; TAC1R
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.[1]


Tachykinins are a family of neuropeptides that share the same hydrophobic C-terminal region with the amino acid sequence Phe-X-Gly-Leu-Met-NH2, where X represents a hydrophobic residue that is either an aromatic or a beta-branched aliphatic. The N-terminal region varies between different tachykinins.[2][3][4] The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles.[4] Substance P is the most researched and potent member of the tachykinin family. It is an undecapeptide with the amino acid sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2.[2] SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK1 receptor.[3]

Tachykinin NK1 receptor[5] consists of 407 amino acid residues, and it has a molecular weight of 58.000.[2][6] NK1 receptor, as well as the other tachykinin receptors, is made of seven hydrophobic transmembrane (TM) domains with three extracellular and three intracellular loops, an amino-terminus and a cytoplasmic carboxy-terminus. The loops have functional sites, including two cysteines amino acids for a disulfide bridge, Asp-Arg-Tyr, which is responsible for association with arrestin and, Lys/Arg-Lys/Arg-X-X-Lys/Arg, which interacts with G-proteins.[5][6]

Distribution and function

The NK1 receptor can be found in both the central and peripheral nervous system. It is present in neurons, brainstem, vascular endothelial cells, muscle, gastrointestinal tracts, genitourinary tract, pulmonary tissue, thyroid gland and different types of immune cells.[5][7][4][6] The binding of SP to the NK1 receptor has been associated with the transmission of stress signals and pain, the contraction of smooth muscles and inflammation.[8] NK1 receptor antagonists have also been studied in migraine, emesis and psychiatric disorders. In fact, aprepitant has been proved effective in a number of pathophysiological models of anxiety and depression.[9] Other diseases in which the NK1 receptor system is involved include asthma, rheumatoid arthritis and gastrointestinal disorders.[10]


SP is synthesized by neurons and transported to synaptic vesicles; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms.[2] 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.[11] It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, it 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.[4]

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.[10] It has been reported that centrally-acting NK1 receptors antagonists, such as CP-99994, inhibit emesis induced by apomorphine and loperimidine, which are two compounds that act through central mechanisms.[7]

Clinical significance

This receptor is considered an attractive drug target, particularly with regards to potential analgesics and anti-depressants.[12][13] It was identified as a candidate in the etiology of bipolar disorder by a 2008 study.[14] Furthermore TACR1 antagonists have shown promise for the treatment in alcoholism.[15] Finally TACR1 antagonists may also have a role as novel antiemetics and hypnotics.[16][17]

Selective ligands

Many selective ligands for NK1 are now available, several of which have gone into clinical use as antiemetics.


  • GR-73632 - potent and selective agonist, EC50 2nM, 5-amino acid polypeptide chain. CAS# 133156-06-6


See also


  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): 1232–1240.  
  2. ^ a b c d 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.  
  3. ^ a b Page, N. M. (August 2005). "New challenges in the study of the mammalian Tachykinins". Peptides 26 (8): 1356–1368.  
  4. ^ a b c d Datar, P.; Srivastava, S.; Coutinho, E.; Govil, G. (2004). "Substance P: Structure, Function, and Therapeutics". Current Topics in Medicinal Chemistry 4 (1): 75–103.  
  5. ^ a b c 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.  
  6. ^ a b c Almeida, T. A.; Rojo, J.; Nieto, P. M.; Hernandez, FM; Martin, J. D.; Candenas, M. L.; Candenas, ML (August 2004). "Tachykinins and Tachykinins Receptors: Structure and Activity Relationships". Current Medicinal Chemistry 11 (15): 2045–81.  
  7. ^ a b Saria, A. (June 1999). receptor in the brain: pharmacology and putative functions"1"The Tachykinin NK. European Journal of Pharmacology 375 (1–3): 51–60.  
  8. ^ Seto, S.; Tanioka, A.; Ikeda, M.; Izawa, S. (March 2005). antagonists"1"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 NK. Bioorganic and Medicinal Chemistry Letters 15 (5): 1479–1484.  
  9. ^ Quartara, L.; Altamura, M. (August 2006). "Tachykinin receptors antagonists: From research to clinic". Current Drug Targets 7 (8): 975–992.  
  10. ^ a b Humphrey, J. M. (2003). "Medicinal Chemistry of Selective Neurokinin-1 Antagonists". Current Topics in Medicinal Chemistry 3 (12): 1423–1435.  
  11. ^ Quartara, L.; Maggi, C. A. (December 1997). receptor. Part I: Ligands and mechanisms of cellular activation"1"The tachykinin NK. Neuropeptides 31 (6): 537–563.  
  12. ^ Humphrey JM (2003). "Medicinal chemistry of selective neurokinin-1 antagonists". Current Topics in Medicinal Chemistry 3 (12): 1423–1435.  
  13. ^ 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". Journal of Neuroscience 29 (1): 222–233.  
  14. ^ 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.  
  15. ^ 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 319 (5869): 1536–1539.  
  16. ^ Ratti, E; et al. (December 2013). "Efficacy of vestipitant, a neurokinin-1 receptor antagonist, in primary insomnia.". Sleep (2013) 36 (12): 1823–30.  
  17. ^ Jordan K (2006). "Neurokinin-1-receptor antagonists: a new approach in antiemetic therapy". Onkologie 29 (1–2): 39–43.  

Further reading

External links

This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.

Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.