Tachykinin receptor 1 explained

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]

Structure

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. The term tachykinin originates in the rapid onset of action caused by the peptides in smooth muscles.

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. SP binds to all three of the tachykinin receptors, but it binds most strongly to the NK₁ receptor.

The tachykinin NK₁ receptor consists of 407 amino acid residues, and it has a molecular weight of 58,000. 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 for a disulfide bridge, Asp-Arg-Tyr, responsible for association with arrestin, and Lys/Arg-Lys/Arg-X-X-Lys/Arg, which interacts with G-proteins. 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.^[2]

Function

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. 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. Other diseases in which the NK₁ receptor system is involved include asthma, rheumatoid arthritis, and gastrointestinal disorders.

Tissue distribution

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.

Mechanisms of action

SP is synthesized by neurons and transported to synaptic vesicles; the release of SP is accomplished through the depolarizing action of calcium-dependent mechanisms. 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.

There are three well-defined, independent second messenger systems:

1. Stimulation via phospholipase C, leading to phosphatidyl inositol turnover and Ca mobilization from both intra- and extracellular sources.
2. Arachidonic acid mobilization via phospholipase A2.
3. cAMP accumulation via stimulation of adenylate cyclase.

It has also been reported that SP elicits interleukin-1 (IL-1) production in macrophages, sensitizes neutrophils, and enhances 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 also secretes catecholamines and plays a role in the regulation of blood pressure and hypertension. Likewise, SP is known to bind to N-methyl-D-aspartate (NMDA) receptors, 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.

Clinical significance

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

This receptor is considered an attractive drug target, particularly with regards to potential analgesics and anti-depressants.^{[3] [4]} It is also a potential treatment for alcoholism and opioid addiction.^[5] In addition, it has been identified as a candidate in the etiology of bipolar disorder.^[6] Finally NK1R antagonists may also have a role as novel antiemetics^[7] and hypnotics.^{[8] [9]}

Neurokinin receptor 1 (NK-1R) also plays a significant role in cancer progression. NK-1R is overexpressed in various cancer types and is activated by substance P (SP).^{[10] [11]} This activation promotes tumor cell proliferation, migration, and invasion while inhibiting apoptosis.^[12] The SP/NK-1R system is involved in angiogenesis, chronic inflammation, and the Warburg effect, all of which contribute to tumor growth. NK-1R antagonists, such as aprepitant, have shown promise as potential anticancer treatments by inhibiting tumor growth, inducing apoptosis, and blocking metastasis.^[13] The overexpression of NK-1R in tumors may also serve as a prognostic biomarker.

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

• Aprepitant
• Casopitant
• Elinzanetant
• Ezlopitant
• Fosaprepitant
• Lanepitant
• Maropitant
• Vestipitant
• L-733,060
• L-741,671
• L-742,694
• RP-67580 - potent and selective antagonist, 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/Vofopitant
• TAK-637
• T-2328

See also

• NK1 receptor antagonist
• Tachykinin receptor
• Discovery and development of neurokinin 1 receptor antagonists

Further reading

• Burcher E . The study of tachykinin receptors . Clinical and Experimental Pharmacology & Physiology . 16 . 6 . 539–543 . June 1989 . 2548782 . 10.1111/j.1440-1681.1989.tb01602.x . 30578296 .
• Kowall NW, Quigley BJ, Krause JE, Lu F, Kosofsky BE, Ferrante RJ . Substance P and substance P receptor histochemistry in human neurodegenerative diseases . Regulatory Peptides . 46 . 1–2 . 174–185 . July 1993 . 7692486 . 10.1016/0167-0115(93)90028-7 . 54379670 .
• Patacchini R, Maggi CA . Peripheral tachykinin receptors as targets for new drugs . European Journal of Pharmacology . 429 . 1–3 . 13–21 . October 2001 . 11698023 . 10.1016/S0014-2999(01)01301-2 .
• Saito R, Takano Y, Kamiya HO . Roles of substance P and NK(1) receptor in the brainstem in the development of emesis . Journal of Pharmacological Sciences . 91 . 2 . 87–94 . February 2003 . 12686752 . 10.1254/jphs.91.87 . free .
• Fong TM, Yu H, Huang RR, Strader CD . The extracellular domain of the neurokinin-1 receptor is required for high-affinity binding of peptides . Biochemistry . 31 . 47 . 11806–11811 . December 1992 . 1280161 . 10.1021/bi00162a019 .
• Fong TM, Huang RR, Strader CD . Localization of agonist and antagonist binding domains of the human neurokinin-1 receptor . The Journal of Biological Chemistry . 267 . 36 . 25664–25667 . December 1992 . 1281469 . 10.1016/S0021-9258(18)35657-6 . free .
• Fong TM, Anderson SA, Yu H, Huang RR, Strader CD . Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor . Molecular Pharmacology . 41 . 1 . 24–30 . January 1992 . 1310144 .
• Takahashi K, Tanaka A, Hara M, Nakanishi S . The primary structure and gene organization of human substance P and neuromedin K receptors . European Journal of Biochemistry . 204 . 3 . 1025–1033 . March 1992 . 1312928 . 10.1111/j.1432-1033.1992.tb16724.x .
• Walsh DA, Mapp PI, Wharton J, Rutherford RA, Kidd BL, Revell PA, Blake DR, Polak JM . Localisation and characterisation of substance P binding to human synovial tissue in rheumatoid arthritis . Annals of the Rheumatic Diseases . 51 . 3 . 313–317 . March 1992 . 1374227 . 1004650 . 10.1136/ard.51.3.313 .
• Gerard NP, Garraway LA, Eddy RL, Shows TB, Iijima H, Paquet JL, Gerard C . Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones . Biochemistry . 30 . 44 . 10640–10646 . November 1991 . 1657150 . 10.1021/bi00108a006 .
• Hopkins B, Powell SJ, Danks P, Briggs I, Graham A . Isolation and characterisation of the human lung NK-1 receptor cDNA . Biochemical and Biophysical Research Communications . 180 . 2 . 1110–1117 . October 1991 . 1659396 . 10.1016/S0006-291X(05)81181-7 .
• Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE . Molecular cloning, structural characterization and functional expression of the human substance P receptor . Biochemical and Biophysical Research Communications . 179 . 3 . 1232–1240 . September 1991 . 1718267 . 10.1016/0006-291X(91)91704-G .
• Giuliani S, Barbanti G, Turini D, Quartara L, Rovero P, Giachetti A, Maggi CA . NK2 tachykinin receptors and contraction of circular muscle of the human colon: characterization of the NK2 receptor subtype . European Journal of Pharmacology . 203 . 3 . 365–370 . October 1991 . 1723045 . 10.1016/0014-2999(91)90892-T .
• Ichinose H, Katoh S, Sueoka T, Titani K, Fujita K, Nagatsu T . Cloning and sequencing of cDNA encoding human sepiapterin reductase--an enzyme involved in tetrahydrobiopterin biosynthesis . Biochemical and Biophysical Research Communications . 179 . 1 . 183–189 . August 1991 . 1883349 . 10.1016/0006-291X(91)91352-D .
• Thöny B, Heizmann CW, Mattei MG . Human GTP-cyclohydrolase I gene and sepiapterin reductase gene map to region 14q21-q22 and 2p14-p12, respectively, by in situ hybridization . Genomics . 26 . 1 . 168–170 . March 1995 . 7782081 . 10.1016/0888-7543(95)80101-Q .
• Fong TM, Cascieri MA, Yu H, Bansal A, Swain C, Strader CD . Amino-aromatic interaction between histidine 197 of the neurokinin-1 receptor and CP 96345 . Nature . 362 . 6418 . 350–353 . March 1993 . 8384323 . 10.1038/362350a0 . 4339311 . 1993Natur.362..350M .
• Derocq JM, Ségui M, Blazy C, Emonds-Alt X, Le Fur G, Brelire JC, Casellas P . Effect of substance P on cytokine production by human astrocytic cells and blood mononuclear cells: characterization of novel tachykinin receptor antagonists . FEBS Letters . 399 . 3 . 321–325 . December 1996 . 8985172 . 10.1016/S0014-5793(96)01346-4 . 84912440 . 1996FEBSL.399..321D .
• De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ, Laird JM, Belmonte C, Cervero F, Hunt SP . Altered nociception, analgesia and aggression in mice lacking the receptor for substance P . Nature . 392 . 6674 . 394–397 . March 1998 . 9537323 . 10.1038/32904 . 4324247 . 1998Natur.392..394D .

External links

• Web site: Tachykinin Receptors: NK₁ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2007-10-25 . 2011-05-16 . https://web.archive.org/web/20110516084923/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=3029 . dead .

Notes and References

1. Takeda Y, Chou KB, Takeda J, Sachais BS, Krause JE . Molecular cloning, structural characterization and functional expression of the human substance P receptor . Biochemical and Biophysical Research Communications . 179 . 3 . 1232–1240 . September 1991 . 1718267 . 10.1016/0006-291X(91)91704-G .
2. Book: Graefe SB, Mohiuddin SS . Biochemistry, Substance P . April 2022 . StatPearls Publishing . Treasure Island, FL . 32119470 . 28 January 2023 .
3. Humphrey JM . Medicinal chemistry of selective neurokinin-1 antagonists . Current Topics in Medicinal Chemistry . 3 . 12 . 1423–1435 . 2003 . 12871173 . 10.2174/1568026033451925 .
4. Duffy RA . Potential therapeutic targets for neurokinin-1 receptor antagonists . Expert Opinion on Emerging Drugs . 9 . 1 . 9–21 . May 2004 . 15155133 . 10.1517/eoed.9.1.9.32956 .
5. Schank JR . The neurokinin-1 receptor in addictive processes . The Journal of Pharmacology and Experimental Therapeutics . 351 . 1 . 2–8 . October 2014 . 25038175 . 10.1124/jpet.113.210799 . 16533561 .
6. Perlis RH, Purcell S, Fagerness J, Kirby A, Petryshen TL, Fan J, Sklar P . Family-based association study of lithium-related and other candidate genes in bipolar disorder . Archives of General Psychiatry . 65 . 1 . 53–61 . January 2008 . 18180429 . 10.1001/archgenpsychiatry.2007.15 .
7. Munoz M, Covenas R, Esteban F, Redondo M . The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs . Journal of Biosciences . 40 . 2 . 441–463 . June 2015 . 25963269 . 10.1007/s12038-015-9530-8 . 3048287 .
8. Brasure M, MacDonald R, Fuchs E, Olson CM, Carlyle M, Diem S, Koffel E, Khawaja IS, Ouellette J, Butler M, Kane RL, Wilt TJ . Management of Insomnia Disorder . Comparative Effectiveness Reviews . 159 . 2015 . 26844312 .
9. Jordan K . Neurokinin-1-receptor antagonists: a new approach in antiemetic therapy . Onkologie . 29 . 1–2 . 39–43 . February 2006 . 16514255 . 10.1159/000089800 . 34016787 .
10. Esteban F, Ramos-García P, Muñoz M, González-Moles MÁ . Substance P and Neurokinin 1 Receptor in Chronic Inflammation and Cancer of the Head and Neck: A Review of the Literature . International Journal of Environmental Research and Public Health . 19 . 1 . 375 . December 2021 . 35010633 . 8751191 . 10.3390/ijerph19010375 . free .
11. Coveñas R, Muñoz M . Involvement of the Substance P/Neurokinin-1 Receptor System in Cancer . Cancers . 14 . 14 . 3539 . July 2022 . 35884599 . 9317685 . 10.3390/cancers14143539 . free .
12. Muñoz M, Coveñas R . Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach . Saudi Journal of Gastroenterology . 22 . 4 . 260–268 . 2016 . 27488320 . 4991196 . 10.4103/1319-3767.187601 . free .
13. Muñoz M, González-Ortega A, Salinas-Martín MV, Carranza A, Garcia-Recio S, Almendro V, Coveñas R . The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer . International Journal of Oncology . 45 . 4 . 1658–1672 . October 2014 . 25175857 . 10.3892/ijo.2014.2565 .