The Neurokinin-1 Receptor: Structure Dynamics and Signaling: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Francisco D. Rodríguez
,
Rafael Coveñas

Substance P (SP), the first isolated neuropeptide, belongs to the family of tachykinin peptides and is the natural ligand of neurokinin-1 receptors (NK-1R), also named SP receptors. The undecapeptide activates the receptor after specifically binding to the protein and triggers intracellular signals leading to different biochemical events and subsequent physiological responses. 

  • substance P
  • neurokinin-1 receptors (NK-1R)
  • NK-1R antagonists

1. G Protein-Coupled Receptors (GPCRs)

G protein-coupled receptors (GPCRs) are abundant and ubiquitous membrane proteins that respond to stimuli from photons to ions, small organic compounds, peptides, and macromolecules. They are responsible for multiple cellular responses and share a serpentine architecture with a package of seven transmembrane helices, alternate intracellular and extracellular loops, the C-terminus lying in the cytoplasm, and the N-terminus expanding towards the extracellular space [1][2][3][4][5][6][7]. GPCRs activate different G protein and β-arrestin-dependent mechanisms that control many physiological and pathological outcomes [8] related to immune responses, mood, cognition, blood pressure control, pain control, taste, vision, and olfaction [6][9][10][11]. Signaling can also occur via endosomal membranes that facilitate the activation of localized signals [12][13][14]. The group is subdivided into classes considering their sequences’ similarities and structural features: A (rhodopsin), B (secretin), B2 (adhesion), C (glutamate receptors), D1 (Ste2-like fungal pheromone), family F (frizzled, FZD, and smoothened, SMO), and T (taste) [10][15]. Extensive and meticulous structural studies of GPCRs provide essential information that allows for a better understanding of their function. They also improved drug design based on the knowledge of protein conformational movements linked to activation and inactivation states and biased agonist signaling [2][10][16][17][18]. X-ray crystallography studies, molecular dynamics simulations, and the mutational analysis of allosteric interfaces with hydrogen bonding networks in transmembrane helices determine states of activity that trigger intracellular signaling [6][7][19][20][21]. Updated information on the structural studies of GPCRs can be found in the GPCRs database [1][15]. GPCRs serve as a target for pharmacological intervention. Approximately 35% of officially approved drugs target GPCRs directly or GPCR-associated proteins [22][23]. The list may grow more prominent due to new methods of drug design exploration based on novel receptor regulation concepts, allosteric changes, biased signaling, and receptor heteromerization [24][25][26][27]. Additionally, post-translational modifications (phosphorylation, glycosylation, ubiquitination, and palmitoylation) influence receptor folding, dimerization, and function [28]. Soundly, these modifications should also be focused on when studying the pharmacological manipulation of GPCRs.
Class A GPCRs (to which NK-1 receptors belong) are the most abundant and studied. They have an enormous influence on human physiology and pathology. Agonist binding to these receptors activates G protein recruitment by moving helix number 6 towards the exterior of the receptor bundle caused by a common activation mechanism affecting specific residues [18]. The first structures defined with X-ray diffraction data were bovine rhodopsin [29] and human β-adrenergic receptors [12][30]. More than a hundred structures of GPCRs have been resolved to date. Conserved sequence motifs, such as D(E)R3.50Y in TM3 and D/E6.30 in TM6, are responsible for the inactivation state of the receptors by establishing an ionic bridge tightening TM3 and TM6 together, thus preventing the flexible outward movement of TM6 necessary for activation and signaling.

2. NK-1R Signaling Pathways

The NK-1 receptor belongs to class A of GPCRs. Upon activation, it signals through different pathways depending on its intrinsic performance, topology within the membrane bilayer, tissue localization, and the type of ligand. Agonist ligands of NK-1R include SP, SP analogs, and neurokinin A (NKA) [31][32][33][34]. The main signaling routes activate Gq and Gs heterotrimeric proteins, causing intracellular variations in second messenger concentrations, such as calcium, cAMP, or IP3 [35][36]. Figure 1 depicts the main signaling pathways activated by NK-1 receptors, leading to operative protein phosphorylation cascades and metabolic regulations responsible for physiological and pathological consequences.
Figure 1. Intracellular NK-1R signaling pathways turned on after binding SP and activating different alpha subunits (Gq and Gs, mainly) and beta-gamma dimers of heterotrimeric G proteins (the structure of NK-1R in green is from the Protein Data Bank [37], PDB Id. 2KS9) [38]. Abbreviations: AC (adenylyl cyclase), cAMP (cyclic 3′-5′ adenosine monophosphate), DAG (diacylglycerol), ER (endoplasmic reticulum), FZ (frizzled), GRK (G protein-coupled receptor kinase), IP3 (inositol 1,4,5 trisphosphate), LRP 5/6 (low-density lipoprotein receptor-related protein), MAPK (mitogen-activated protein kinase), NK-1R (neurokinin-1 receptor), PI3K (phosphatidylinositol 3-kinase), PKA (protein kinase A), PKC (protein kinase C), PLC (phospholipase C), and Wnt (wingless-related integration site) [35][39][40][41][42][43][44][45][46][47][48].
The observed differential activation of NK-1R signaling cascades by agonists may be caused by structural coupling between the receptor and agonist, where efficacy and selectivity lie in different architectural settings. The interface formed by amino acid positions E2.50, S3.39, and N7.49 sets in a net of hydrogen bonds and facilitates receptor conformations leading to biased receptor activation (Gs, Gq, and β-arrestin) [49]. In this hydrogen bond network built by the amino acid lateral chains, the alanine substitution of E2.50 abolished SP-activated Gq signaling measured by the accumulation of inositol 1, 4,5 trisphosphate (IP3). However, the alanine substitution of N7.49 and S3.39 had a marginal effect on Gq stimulation.
SP and neurokinin A (NKA) and neurokinin B (NKB) bind NK-1 receptors; however, differences in the charge distribution and amino acid composition of the peptides and their interaction with the anionic surface formed by acidic residues in extracellular loops 2 and 3 favor SP binding (higher affinity) over the other two tachykinins [50]. The structural resolution of NK-1 receptors bound to Gs and Gq proteins contributed to determining that the receptor similarly binds to both G proteins [50]. However, the binding to Gq is slightly favored and accords with the observed preference of Gq over Gs signaling [51]. Mutagenesis experiments and the structural dynamics analysis of ligand–receptor interactions [31][32][52] showed that SP and its truncated form SP6-11 (lacking the N-terminal region of the undecapeptide) triggered calcium signaling with similar potency when bound to wild-type NK-1 receptors. However, NKA and SP6-11 induce a weaker cAMP accumulation response than SP. Additionally, experiments with NK-1R bearing conservative mutations of amino acids establishing hydrogen bonding nets deeper inside the pocket (N852.57, N892.61, H1083.28, and Y2877.35) with the C-terminal region of SP (Figure 2) did not affect the potency and maximal response of the undecapeptide. In contrast, truncated SP6-11-dependent responses significantly decreased [52].
Receptors 01 00004 g008 550
Figure 2. Weak bonding interactions of different amino acid residues (yellow) coming into contact with the C-terminal region of SP (blue) deep inside the orthosteric pocket of the NK-1 receptor (gray) (PDB Id: 7RMG [52]). Conservative mutations of the depicted positions do not affect the SP-induced increase in intracellular Ca2+ concentrations. The figure also indicates residue M11 of the undecapeptide. The structure is from the Protein Data Bank [53], drawn with the Mol* software [54].
The findings point out that the calcium signaling depended on the interaction of the C-terminal region of SP with the receptor. However, the findings also showed that contact between the central and N-terminal parts of SP with the extracellular domains of NK-1R (ECL2 and N-terminus area) is essential for signaling through Gs and not only for ligand recognition and selectivity. Molecular dynamics simulations reported that the residues F7 and M11 in SP6-11-truncated peptide adopt more orientations than F7 and M11 in SP undecapeptide and establish differential contacts with TM7 and TM6 of the NK-1R [52]. It is worth noting that preferential Gq activation obtained with SP6-11 reinforces the assumption that connections between the N-terminal region of SP with the exterior of NK-1R determined receptor activation-dependent signaling.
Other GPCRs also exhibit biased agonism responsible for activating singular intracellular metabolic reactions, producing a signaling signature at a given time and in a particular target cell [20][55].
The truncated NK-1 receptor isoform lacks the intracellular C-terminal region [56][57]. Full (NK-1R-F) and truncated NK-1 (NK-1R-T) receptor isoforms display functional differences affecting intracellular signaling [39]. The exclusion of the C-terminal tail impairs receptor internalization, making the protein resistant to desensitization [56]. Additionally, the interaction with transducer G proteins is weaker, and calcium release, protein kinase C (PKC) activation, and other phosphorylation events appear delayed [58][59][60].
The so-called canonical Wnt/β-catenin signaling pathways encompass a group of membrane-bound and intracellular proteins, and the route is closely related to the control of immunomodulation and cell proliferation. The activation of the FZ/LRP 5/6 complex (frizzled/low-density lipoprotein receptor-related protein 5/6) by secreted cysteine-rich glycoproteins Wnt (wingless-related integration site) (see Figure 1) mobilizes an effector G protein, disrupts the Axin-GSK3-APC-CK1 complex and impedes the phosphorylation of β-catenin by the kinases GSK-3β and CK1 (casein kinase 1). Consequently, β-catenin accumulates in the cytosol and moves to the nucleus, where it associates with TCFs/LEF (T-cell factor/lymphoid-enhancer-binding factor) proteins and other transcription factors and co-triggers the transcription of target genes by binding to specific promoter sequences [47][61][62][63][64]. β-catenin may also translocate to the membrane and stabilize it by building cell adhesion complexes [64][65].
Experimental studies using agonists and antagonists of NK-1R showed that the agonist turning-on of NK-1R induced an increased expression of β-catenin and GSK3β and diminished the expression of DKK1 (Dickkopf 1), an inhibitor of Wnt [66]. Additionally, selective antagonists of NK-1 receptors inhibited cell proliferation in several experimental scenes by influencing Wnt/β-catenin pathways [40][65][67][68].
The NK-1R system controls numerous intracellular processes, including cell growth, cytoskeletal organization, metabolic reaction, or gene expression through biochemical reactions that contribute to cell homeostasis [69]. Malfunction of the receptor induces dysregulation of intracellular signaling cascades, and disease may appear. NK-1R-triggered signaling complexes participating in cell disruption led to inflammation, calcium overloads, altered cell metabolism and growth, and disrupted cell migration conveying to cancer, pain, psychiatric disorders, and other pathologies. Molecular complexes responsible include the Wnt/β-catenin [40], β-arrestins scaffolds [69], JNK and p38/MAPK [70], NF-kB [70][71], PKCδ/ERK/P65 [72], or metalloproteases MMP-2/MMP-9 [73], to mention a few (Figure 1).
Aside from fine structural studies revealing activated and inactivated conformations of the receptors induced by movements of receptor domains, determining the binding kinetics of both agonist and antagonist ligands deserves attention to ascertain signal transduction outcomes and determine new drugs’ specificity, efficacy, modulation, and potency [74].

This entry is adapted from the peer-reviewed paper 10.3390/receptors1010004

References

  1. Pándy-Szekeres, G.; Esguerra, M.; Hauser, A.S.; Caroli, J.; Munk, C.; Pilger, S.; Keserű, G.M.; Kooistra, A.J.; Gloriam, D.E. The G protein database, GproteinDb. Nucleic Acids Res. 2022, 50, D518–D525.
  2. Hilger, D. The role of structural dynamics in GPCR-mediated signaling. FEBS J. 2021, 288, 2461–2489.
  3. Fredriksson, R.; Lagerström, M.C.; Lundin, L.G.; Schiöth, H.B. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 2003, 63, 1256–1272.
  4. Huang, S.K.; Prosser, R.S. Dynamics and Mechanistic Underpinnings to Pharmacology of Class A GPCRs—An NMR Perspective. Am. J. Physiol. Cell. Physiol. 2022, 322, C739–C753.
  5. White, K.L.; Eddy, M.T.; Gao, Z.-G.; Han, G.W.; Lian, T.; Deary, A.; Patel, N.; Jacobson, K.A.; Katritch, V.; Stevens, R.C. Structural Connection between Activation Microswitch and Allosteric Sodium Site in GPCR Signaling. Structure 2018, 26, 259–269.
  6. Rosenbaum, D.M.; Rasmussen, S.G.; Kobilka, B.K. The structure and function of G-protein-coupled receptors. Nature 2009, 459, 356–363.
  7. Katritch, V.; Cherezov, V.; Stevens, R.C. Structure-Function of the G Protein–Coupled Receptor Superfamily. Annu. Rev. Pharmacol. Toxicol. 2013, 53, 531–556.
  8. Defea, K. Beta-arrestins and heterotrimeric G-proteins: Collaborators and competitors in signal transduction. Br. J. Pharmacol. 2008, 153 (Suppl. 1), 298.
  9. Salon, J.A.; Lodowski, D.T.; Palczewski, K. The Significance of G Protein-Coupled Receptor Crystallography for Drug Discovery. Pharmacol. Rev. 2011, 63, 901–937.
  10. Lee, Y.; Basith, S.; Choi, S. Recent Advances in Structure-Based Drug Design Targeting Class A G Protein-Coupled Receptors Utilizing Crystal Structures and Computational Simulations. J. Med. Chem. 2017, 61, 1–46.
  11. Mantas, I.; Saarinen, M.; Xu, Z.D.; Svenningsson, P. Update on GPCR-based targets for the development of novel antidepressants. Mol. Psychiatry 2022, 27, 534–558.
  12. Rasmussen, S.G.; DeVree, B.T.; Zou, Y.; Kruse, A.C.; Chung, K.Y.; Kobilka, T.S.; Thian, F.S.; Chae, P.S.; Pardon, E.; Calinski, D.; et al. Crystal structure of the β2 adrenergic receptor–Gs protein complex. Nature 2011, 477, 549–555.
  13. Eichel, K.; von Zastrow, M. Subcellular Organization of GPCR Signaling. Trends Pharmacol. Sci. 2018, 39, 200–208.
  14. Sutkeviciute, I.; Vilardaga, J.-P. Structural insights into emergent signaling modes of G protein–coupled receptors. J. Biol. Chem. 2020, 295, 11626–11642.
  15. GPCR Database. GPCR Database. 2022. Available online: https://gpcrdb.org (accessed on 20 September 2022).
  16. Wold, E.A.; Chen, J.; Cunningham, K.A.; Zhou, J. Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts. J. Med. Chem. 2019, 62, 88–127.
  17. Zhang, D.; Zhao, Q.; Wu, B. Structural Studies of G Protein-Coupled Receptors. Mol. Cells 2015, 38, 836–842.
  18. Zhou, Q.; Yang, D.; Wu, M.; Guo, Y.; Guo, W.; Zhong, L.; Cai, X.; Dai, A.; Jang, W.; Shakhnovich, E.I.; et al. Common activation mechanism of class A GPCRs. eLife 2019, 8, e50279.
  19. Nygaard, R.; Frimurer, T.M.; Holst, B.; Rosenkilde, M.M.; Schwartz, T.W. Ligand binding and micro-switches in 7TM receptor structures. Trends Pharmacol. Sci. 2009, 30, 249–259.
  20. Wisler, J.W.; Xiao, K.; Thomsen, A.R.; Lefkowitz, R.J. Recent developments in biased agonism. Curr. Opin. Cell Biol. 2013, 27, 18–24.
  21. Rosenkilde, M.M.; Smit, M.J.; Waldhoer, M. Structure, function and physiological consequences of virally encoded chemokine seven transmembrane receptors. Br. J. Pharmacol. 2008, 153 (Suppl. 1), 154.
  22. Sriram, K.; Insel, P.A. G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol. Pharmacol. 2018, 93, 251–258.
  23. Hauser, A.S.; Attwood, M.M.; Rask-Andersen, M.; Schiöth, H.B.; Gloriam, D.E. Trends in GPCR drug discovery: New agents, targets and indications. Nat. Rev. Drug Discov. 2017, 16, 829–842.
  24. Franco, R.; Martinez-Pinilla, E.; Lanciego, J.L.; Navarro, G. Basic Pharmacological and Structural Evidence for Class A G-Protein-Coupled Receptor Heteromerization. Front. Pharmacol. 2016, 7, 76.
  25. Gaitonde, S.A.; González-Maeso, J. Contribution of heteromerization to G protein-coupled receptor function. Curr. Opin. Pharmacol. 2017, 32, 23–31.
  26. Gomes, I.; Ayoub, M.A.; Fujita, W.; Jaeger, W.C.; Pfleger, K.D.; Devi, L.A. G Protein–Coupled Receptor Heteromers. Annu. Rev. Pharmacol. Toxicol. 2016, 56, 403–425.
  27. Pfeiffer, M.; Kirscht, S.; Stumm, R.; Koch, T.; Wu, D.; Laugsch, M.; Schröder, H.; Höllt, V.; Schulz, S. Heterodimerization of substance P and mu-opioid receptors regulates receptor trafficking and resensitization. J. Biol. Chem. 2003, 278, 51630–51637.
  28. Zhang, B.; Li, S.; Shui, W. Post-Translational Modifications of G Protein–Coupled Receptors Revealed by Proteomics and Structural Biology. Front. Chem. 2022, 10, 843502.
  29. Palczewski, K.; Kumasaka, T.; Hori, T.; Behnke, C.A.; Motoshima, H.; Fox, B.A.; Le Trong, I.; Teller, D.C.; Okada, T.; Stenkamp, R.E.; et al. Crystal Structure of Rhodopsin: A G Protein-Coupled Receptor. Science 2000, 289, 739–745.
  30. Cherezov, V.; Rosenbaum, D.M.; Stevens, R.C.; Hanson, M.A.; Rasmusen, S.G.F.; Thian, S.S.; Kobilka, T.S.; Choi, H.; Kuhn, P.; Weis, W.I.; et al. High-Resolution Crystal Structure of an Engineered Human β2 -Adrenergic G Protein–Coupled Receptor. Science 2007, 318, 1258–1265.
  31. Sagan, S.; Chassaing, G.; Pradier, L.; Lavielle, S. Tachykinin peptides affect differently the second messenger pathways after binding to CHO-expressed human NK-1 receptors. J. Pharmacol. Exp. Ther. 1996, 276, 1039–1048.
  32. Riitano, D.; Werge, T.M.; Costa, T. A Mutation Changes Ligand Selectivity and Transmembrane Signaling Preference of the Neurokinin-1 Receptor. J. Biol. Chem. 1997, 272, 7646–7655.
  33. Sakurada, T.; Yamada, T.; Tan-No, K.; Manome, Y.; Sakurada, S.; Kisara, K.; Ohba, M. Differential effects of substance P analogs on neurokinin 1 receptor agonists in the mouse spinal cord. J. Pharmacol. Exp. Ther. 1991, 259, 205–210.
  34. Trafton, J.A.; Abbadie, C.; Basbaum, A.I. Differential Contribution of Substance P and Neurokinin A to Spinal Cord Neurokinin-1 Receptor Signaling in the Rat. J. Neurosci. 2001, 21, 3656–3664.
  35. Calebiro, D.; Godbole, A. Internalization of G-protein-coupled receptors: Implication in receptor function, physiology and diseases. Best Pract. Res. Clin. Endocrinol. Metab. 2018, 32, 83–91.
  36. Garcia-Recio, S.; Gascón, P. Biological and Pharmacological Aspects of the NK1-Receptor. BioMed Res. Int. 2015, 2015, 495704.
  37. Borbély, É.; Helyes, Z. Role of hemokinin-1 in health and disease. Neuropeptides 2017, 64, 9–17.
  38. Zhang, Y.; Lu, L.; Furlonger, C.; Wu, G.E.; Paige, C.J. Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis. Nat. Immunol. 2000, 1, 392–397.
  39. Spitsin, S.; Pappa, V.; Douglas, S.D. Truncation of neurokinin-1 receptor-Negative regulation of substance P signaling. J. Leukoc. Biol. 2018, 103, 1043–1051.
  40. Sha, Y.-L.; Liu, S.; Yan, W.-W.; Dong, B. Wnt/β-catenin signaling as a useful therapeutic target in hepatoblastoma. Biosci. Rep. 2019, 39, BSR20192466.
  41. Krause, J.E.; Bu, J.Y.; Takeda, Y.; Blount, P.; Raddatz, R.; Sachais, B.S.; Chou, K.B.; Takeda, J.; McCarson, K.; DiMaggio, D. Structure, expression and second messenger-mediated regulation of the human and rat substance P receptors and their genes. Regul. Pept. 1993, 46, 59–66.
  42. Quartara, L.; Maggi, C.A. The tachykinin NK1 receptor. Part I: Ligands and mechanisms of cellular activation. Neuropeptides 1997, 31, 537–563.
  43. Steinhoff, M.S.; von Mentzer, B.; Geppetti, P.; Pothoulakis, C.; Bunnett, N.W. Tachykinins and Their Receptors: Contributions to Physiological Control and the Mechanisms of Disease. Physiol. Rev. 2014, 94, 265–301.
  44. Zieglgänsberger, W. Substance P and pain chronicity. Cell Tissue Res. 2019, 375, 227–241.
  45. Mistrova, E.; Kruzliak, P.; Chottova Dvorakova, M.C. Role of substance P in the cardiovascular system. Neuropeptides 2016, 58, 41–51.
  46. Ebrahimi, S.; Javid, H.; Alaei, A.; Hashemy, S.I. New insight into the role of substance P/neurokinin-1 receptor system in breast cancer progression and its crosstalk with microRNAs. Clin. Genet. 2020, 98, 322–330.
  47. Javid, H.; Mohammadi, F.; Zahiri, E.; Hashemy, S.I. The emerging role of substance P/neurokinin-1 receptor signaling pathways in growth and development of tumor cells. J. Physiol. Biochem. 2019, 75, 415–421.
  48. Eapen, P.M.; Rao, C.M.; Nampoothiri, M. Crosstalk between neurokinin receptor signaling and neuroinflammation in neurological disorders. Rev. Neurosci. 2018, 30, 233–243.
  49. Valentin-Hansen, L.; Frimurer, T.M.; Mokrosinski, J.; Holliday, N.D.; Schwartz, T.W. Biased Gs Versus Gq Proteins and β-Arrestin Signaling in the NK1 Receptor Determined by Interactions in the Water Hydrogen Bond Network. J. Biol. Chem. 2015, 290, 24495–24508.
  50. Thom, C.; Ehrenmann, J.; Vacca, S.; Waltenspühl, Y.; Schöppe, J.; Medalia, O.; Plückthun, A. Structures of neurokinin 1 receptor in complex with G q and G s proteins reveal substance P binding mode and unique activation features. Sci. Adv. 2021, 7, eabk2872.
  51. Holst, B.; Hastrup, H.; Raffetseder, U.; Martini, L.; Schwartz, T.W. Two Active Molecular Phenotypes of the Tachykinin NK1 Receptor Revealed by G-protein Fusions and Mutagenesis. J. Biol. Chem. 2001, 276, 19793–19799.
  52. Harris, J.A.; Faust, B.; Gondin, A.B.; Dämgen, M.A.; Suomivuori, C.-M.; Veldhuis, N.A.; Cheng, Y.; Dror, R.O.; Thal, D.M.; Manglik, A. Selective G protein signaling driven by substance P–neurokinin receptor dynamics. Nat. Chem. Biol. 2022, 18, 109–115.
  53. PDB. Protein Data Bank (PDB). 2022. Available online: https://pdb101.rcsb.org (accessed on 20 September 2022).
  54. Sehnal, D.; Bittrich, S.; Deshpande, M.; Svobodová, R.; Berka, K.; Bazgier, V.; Velankar, S.; Burley, S.K.; Koča, J.; Rose, A.S. Mol* Viewer: Modern web app for 3D visualization and analysis of large biomolecular structures. Nucleic Acids Res. 2021, 49, W431–W437.
  55. Suomivuori, C.-M.; Latorraca, N.R.; Wingler, L.M.; Eismann, S.; King, M.C.; Kleinhenz, A.L.W.; Skiba, M.A.; Staus, D.P.; Kruse, A.C.; Lefkowitz, R.J.; et al. Molecular mechanism of biased signaling in a prototypical G protein–coupled receptor. Science 2020, 367, 881–887.
  56. Fong, T.M.; Anderson, S.A.; Yu, H.; Huang, R.R.; Strader, C.D. Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor. Mol. Pharmacol. 1992, 41, 24–30.
  57. Kage, R.; Leeman, S.E.; Boyd, N.D. Biochemical Characterization of Two Different Forms of the Substance P Receptor in Rat Submaxillary Gland. J. Neurochem. 1993, 60, 347–351.
  58. Barrett, J.; Canning, B.; Coulson, J.; Dombrowsky, E.; Douglas, S.D.; Fong, T.M.; Heyward, C.Y.; Leeman, S.E.; Remeshwar, P. Tachykinin receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database. IUPHAR/BPS Guide Pharmacol. CITE 2019, 2019, 1–18.
  59. Lai, J.-P.; Lai, S.; Tuluc, F.; Tansky, M.F.; Kilpatrick, L.E.; Leeman, S.E.; Douglas, S.D. Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor. Proc. Natl. Acad. Sci. USA 2008, 105, 12605–12610.
  60. Tuluc, F.; Lai, J.P.; Kilpatrick, L.E.; Evans, D.L.; Douglas, S.D. Neurokinin 1 receptor isoforms and the control of innate immunity. Trends Immunol. 2009, 30, 271–276.
  61. Pai, S.G.; Carneiro, B.A.; Mota, J.M.; Costa, R.; Leite, C.A.; Barroso-Sousa, R.; Kaplan, J.B.; Chae, Y.K.; Giles, F.J. Wnt/beta-catenin pathway: Modulating anticancer immune response. J. Hematol. Oncol. 2017, 10, 101–106.
  62. Fagotto, F. Looking beyond the Wnt pathway for the deep nature of β-catenin. EMBO Rep. 2013, 14, 422–433.
  63. Voronkov, A.; Krauss, S. Wnt/beta-catenin signaling and small molecule inhibitors. Curr. Pharm. Des. 2013, 19, 634–664.
  64. Bienz, M. Beta-Catenin: A pivot between cell adhesion and Wnt signalling. Curr. Biol. 2005, 15, 64.
  65. Garnier, A.; Vykoukal, J.; Hubertus, J.; Alt, E.; von Schweinitz, D.; Kappler, R.; Berger, M.; Ilmer, M. Targeting the neurokinin-1 receptor inhibits growth of human colon cancer cells. Int. J. Oncol. 2015, 47, 151–160.
  66. Zhou, J.; Ling, J.; Song, H.; Lv, B.; Wang, L.; Shang, J.; Wang, Y.; Chang, C.; Ping, F.; Qian, J. Neurokinin-1 receptor is a novel positive regulator of Wnt/β-catenin signaling in melanogenesis. Oncotarget 2016, 7, 81268–81280.
  67. Ilmer, M.; Garnier, A.; Vykoukal, J.; Alt, E.; von Schweinitz, D.; Kappler, R.; Berger, M. Targeting the Neurokinin-1 Receptor Compromises Canonical Wnt Signaling in Hepatoblastoma. Mol. Cancer Ther. 2015, 14, 2712–2721.
  68. Niu, X.-L.; Hou, J.-F.; Li, J.-X. The NK1 receptor antagonist NKP608 inhibits proliferation of human colorectal cancer cells via Wnt signaling pathway. Biol. Res. 2018, 51, 14.
  69. Peterson, Y.K.; Luttrell, L.M. The Diverse Roles of Arrestin Scaffolds in G Protein–Coupled Receptor Signaling. Pharmacol. Rev. 2017, 69, 256–297.
  70. Yang, Y.; Zhou, W.; Xu, X.; Ge, X.; Wang, F.; Zhang, G.-Q.; Miao, L.; Deng, X. Aprepitant Inhibits JNK and p38/MAPK to Attenuate Inflammation and Suppresses Inflammatory Pain. Front. Pharmacol. 2022, 12, 811584.
  71. Singh, S.; Kumaravel, S.; Dhole, S.; Roy, S.; Pavan, V.; Chakraborty, S. Neuropeptide Substance P Enhances Inflammation-Mediated Tumor Signaling Pathways and Migration and Proliferation of Head and Neck Cancers. Indian J. Surg. Oncol. 2021, 12 (Suppl. 1), 93–102.
  72. Chen, Y.; Liu, H.; Zhang, Q.; Luo, Y.; Wu, L.; Zhong, Y.; Tang, Z.; Pu, Y.; Lu, C.; Yin, G.; et al. Cinacalcet Targets the Neurokinin-1 Receptor and Inhibits PKCδ/ERK/P65 Signaling to Alleviate Dextran Sulfate Sodium-Induced Colitis. Front. Pharmacol. 2021, 12, 735194.
  73. Golestaneh, M.; Firoozrai, M.; Javid, H.; Hashemy, S.I. The substance P/neurokinin-1 receptor signaling pathway mediates metastasis in human colorectal SW480 cancer cells. Mol. Biol. Rep. 2022, 49, 4893–4900.
  74. Nederpelt, I.; Kuzikov, M.; De Witte, W.E.A.; Schnider, P.; Tuijt, B.; Gul, S.; Ijzerman, A.P.; De Lange, E.C.M.; Heitman, L.H. From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action. Sci. Rep. 2017, 7, 14169–14174.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
ScholarVision Creations
Feedback