TACR1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTACR1, NK1R, NKIR, SPR, TAC1R, tachykinin receptor 1
External IDsOMIM: 162323 MGI: 98475 HomoloGene: 20288 GeneCards: TACR1
Orthologs
SpeciesHumanMouse
Entrez

6869

21336

Ensembl

ENSG00000115353

ENSMUSG00000030043

UniProt

P25103

P30548

RefSeq (mRNA)

NM_015727
NM_001058

NM_009313

RefSeq (protein)

NP_001049
NP_056542

NP_033339

Location (UCSC)Chr 2: 75.05 – 75.2 MbChr 6: 82.38 – 82.54 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5]

Properties

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.[6][7][8] The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles.[8] Substance P (SP) 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.[6] SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK1 receptor.[7]

Tachykinin NK1 receptor[9] consists of 407 amino acid residues, and it has a molecular weight of 58,000.[6][10] 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.[9][10] The binding site for substance P and other agonists and antagonists is found between the second and third transmembrane domains. The NK-1 receptor is found on human chromosome 2 and is located on the cell's surface as a cytoplasmic receptor.[11]

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.[9][12][8][10] 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.[13] 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.[14] Other diseases in which the NK1 receptor system is involved include asthma, rheumatoid arthritis and gastrointestinal disorders.[15]

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.[6] 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.[16] 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.[8]

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.[15] 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.[12]

Clinical significance

This receptor is considered an attractive drug target, particularly with regards to potential analgesics and anti-depressants.[17][18] It is also a potential treatment for alcoholism and opioid addiction.[19] In addition, it has been identified as a candidate in the etiology of bipolar disorder.[20] Finally NK1R antagonists may also have a role as novel antiemetics[21] and hypnotics.[22][23]

Ligands

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

Agonists

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

Antagonists

See also

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115353 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030043 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE (September 1991). "Molecular cloning, structural characterization and functional expression of the human substance P receptor". Biochemical and Biophysical Research Communications. 179 (3): 1232–1240. doi:10.1016/0006-291X(91)91704-G. PMID 1718267.
  6. 1 2 3 4 Ho WZ, Douglas SD (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. S2CID 14975995.
  7. 1 2 Page NM (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. S2CID 23094292.
  8. 1 2 3 4 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.
  9. 1 2 3 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. PMID 16918325.
  10. 1 2 3 Almeida TA, Rojo J, Nieto PM, Pinto FM, Hernandez M, Martín JD, Candenas ML (August 2004). "Tachykinins and tachykinin receptors: structure and activity relationships". Current Medicinal Chemistry. 11 (15): 2045–2081. doi:10.2174/0929867043364748. PMID 15279567.
  11. ↑ Graefe SB, Mohiuddin SS (April 2022). Biochemistry, Substance P. Treasure Island, FL: StatPearls Publishing. PMID 32119470. Retrieved 28 January 2023.
  12. 1 2 Saria A (June 1999). "The tachykinin NK1 receptor in the brain: pharmacology and putative functions". European Journal of Pharmacology. 375 (1–3): 51–60. doi:10.1016/S0014-2999(99)00259-9. PMID 10443564.
  13. ↑ Seto S, Tanioka A, Ikeda M, Izawa S (March 2005). "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(1) antagonists". Bioorganic & Medicinal Chemistry Letters. 15 (5): 1479–1484. doi:10.1016/j.bmcl.2004.12.091. PMID 15713411.
  14. ↑ Quartara L, Altamura M (August 2006). "Tachykinin receptors antagonists: from research to clinic". Current Drug Targets. 7 (8): 975–992. doi:10.2174/138945006778019381. PMID 16918326.
  15. 1 2 Humphrey JM (2003). "Medicinal chemistry of selective neurokinin-1 antagonists". Current Topics in Medicinal Chemistry. 3 (12): 1423–1435. doi:10.2174/1568026033451925. PMID 12871173.
  16. ↑ Quartara L, Maggi CA (December 1997). "The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation". Neuropeptides. 31 (6): 537–563. doi:10.1016/S0143-4179(97)90001-9. PMID 9574822. S2CID 13735836.
  17. ↑ Humphrey JM (2003). "Medicinal chemistry of selective neurokinin-1 antagonists". Current Topics in Medicinal Chemistry. 3 (12): 1423–1435. doi:10.2174/1568026033451925. PMID 12871173.
  18. ↑ Duffy RA (May 2004). "Potential therapeutic targets for neurokinin-1 receptor antagonists". Expert Opinion on Emerging Drugs. 9 (1): 9–21. doi:10.1517/eoed.9.1.9.32956. PMID 15155133.
  19. ↑ Schank JR (October 2014). "The neurokinin-1 receptor in addictive processes". The Journal of Pharmacology and Experimental Therapeutics. 351 (1): 2–8. doi:10.1124/jpet.113.210799. PMID 25038175. S2CID 16533561.
  20. ↑ 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". Archives of General Psychiatry. 65 (1): 53–61. doi:10.1001/archgenpsychiatry.2007.15. PMID 18180429.
  21. ↑ Munoz M, Covenas R, Esteban F, Redondo M (June 2015). "The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs". Journal of Biosciences. 40 (2): 441–463. doi:10.1007/s12038-015-9530-8. PMID 25963269. S2CID 3048287.
  22. ↑ Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, Koffel E, Khawaja IS, Ouellette J, Butler M, Kane RL, Wilt TJ (2015). "Management of Insomnia Disorder". Comparative Effectiveness Reviews. 159. PMID 26844312.
  23. ↑ Jordan K (February 2006). "Neurokinin-1-receptor antagonists: a new approach in antiemetic therapy". Onkologie. 29 (1–2): 39–43. doi:10.1159/000089800. PMID 16514255. S2CID 34016787.

Further reading

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