Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Neurokinin-1 Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101781

Synonyms

Historical Background

The undecapeptide substance P (SP) belongs to the tachykinin peptide family (hemokinin 1 (HK-1), neurokinin A (NKA), and B (NKB) are also included in this family). This family of peptides exerts many biological actions through three receptors named neurokinin-1, neurokinin-2, and neurokinin-3. The neurokinin-1 receptor (NK-1R) shows a preferential affinity for SP/HK-1, NK-2R for NKA, and NK-3R for NKB (Pennefather et al. 2004). The affinity of the NK-1R for NKA and NKB is, respectively, 100- and 500-fold lower than for SP (Gerard et al. 1991). SP, after binding to the NK-1R, exerts many biological actions (Muñoz and Coveñas 2014). The NK-1R protein is encoded by the TACR1 gene (Takeda et al. 1991). In humans, this gene is located on chromosome 2 and spans 45–60 kb, and it is contained in five exons (Gerard et al. 1991). The NK-1R belongs to the 1 (rhodopsin-like) G protein-coupled receptors (GPCRs) family (also known as seven-transmembrane domain receptors, 7TM receptors or serpentine receptors).

Distribution and Isoforms of the NK-1R

The distribution of the NK-1R is widespread. This receptor has been located in both central and peripheral nervous systems, in the immune system (leucocytes, lymphocytes, monocytes, macrophages), gastrointestinal tract, lung, placenta, thyroid gland, and skin, platelets and endothelial cells, etc. (O’Connor et al. 2004; Muñoz et al. 2010; Muñoz and Coveñas 2014). Moreover, an overexpression of the NK-1R has been reported in cancer cells in comparison with normal cells (Muñoz and Coveñas 2013). This receptor has been located in many human cancer cells such as glioma, neuroblastoma, retinoblastoma, melanoma, hepatoblastoma, osteosarcoma, cholangiocarcinoma, and oral, gastric, colon, pancreatic, lung (small and non-small cells), breast, and endometrial carcinomas (Muñoz and Coveñas 2013). In tumor cells, the NK-1R was observed in both cytoplasm and nucleus.

The NK-1 receptor contains 407 amino acids and has a molecular mass of 46 kDa (Hopkins et al. 1991). It is a seven-transmembrane-helix receptor showing three extracellular (E1, E2, and E3) and three intracellular (C1, C2, C3) loops with the possibility for a fourth loop (C4), due to the palmitoylation of cysteine, seven-transmembrane domains (TM I–VII), and an amino-terminal (extracellular) and a carboxy-terminal (cytoplasmic) domain (Pennefather et al. 2004; García-Recio and Gascón 2015). SP binds to residues 178–183 (Val-Val-Cys-Met-Ile-Glu) located in the middle of the second extracellular loop (E2): a covalent link occurs between the peptide and the methyl group of a methionine residue (Met-181) (Kage et al. 1996) (Fig. 1), whereas C3 is responsible for the binding to the G protein. The C-terminus contains serine/threonine residues, which, once phosphorylated, cause desensitization of the receptor when it is repeatedly activated by SP (DeFea et al. 2000).
Neurokinin-1 Receptor, Fig. 1

Binding sites for SP and NK-1R antagonists

Two isoforms of the NK-1R have been reported: the full-length and the truncated forms. The first (fl-NK-1R) contains 407 amino acids and the second (tr-NK-1R) 311 amino acids (the last 96 amino acids at the C-terminus are lost) (Fong et al. 1992).

The loss of certain C-terminal serine and threonine residues is important for G protein-coupled receptor kinase (GRK) interaction and β-arrestin recruitment for subsequent receptor internalization (DeFea et al. 2000). The tr-NK-1R could be able for prolonging the responses after the binding of ligands because its desensitization and internalization are affected. Due to the different structure of both isoforms, they have a different functional significance, differing in cell signaling capability (Douglas and Leeman 2010). In fact, in colitis-associated cancer, the expression of the tr-NK-1R (but not of the fl-NK-1R) predicted the progression from quiescent colitis to a high-grade dysplasia and cancer (Gillespie et al. 2011). It has been also reported that the tr-NK-1R was overexpressed in human hepatoblastoma cell lines, whereas negligible levels of this receptor were found in human fibroblasts and in nonmalignant HEK-293 cells (Berger et al. 2014).

NK-1R Mechanism of Action: Cell Signaling

SP, after binding to the GPCR NK-1R, induces a change in the Gα subunit, allowing it to exchange GTP for GDP and permitting the dissociation of the Gβγ dimer, inducing the signaling cascade. The hydrolysis of GTP returns the Gα subunit to its inactive state, allowing again the trimeric formation with the Gβγ subunit (Neer 1994) (Fig. 2). There are five subtypes of Gα (Gαs, Gαi, Gαq11, Gα12/13, Gαo) which are associated to the following signaling pathways:
  1. 1.

    Gαs. This subunit produces the activation of the second messenger adenylate cyclase (AC) which catalyzes the conversion of ATP into cyclic adenosine monophosphate cytoplasmic (cAMP): by increasing the level of cAMP the activation of protein kinase A (PKA) occurs (Laniyonu et al. 1988).

     
  2. 2.

    Gαi. It is involved in the inhibition of various types of AC. The increase in the extracellular signal-regulated kinases (ERK)1/2 phosphorylation is through a Gαi pathway, and it is mediated by mitogen-activated protein kinase kinase (MEK)1/2. Moreover, Gαi stimulates the release of [3H]araquidonic acid (Garcia et al. 1994; Lee et al. 2009).

     
  3. 3.

    Gαq11. The effector of the Gαq11 pathway is the phospholipase C-β (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-biphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors located in the membrane of the endoplasmic reticulum (ER) eliciting the release of Ca2+ from the ER, whereas DAG diffuses along the plasma membrane where it may activate a ser/thr kinase called protein kinase C (PKC). Because many isoforms of PKC are also activated by an increase in the intracellular level of Ca2+, both pathways can converge on each other through the same secondary effector (Nakajima et al. 1992).

     
  4. 4.

    Gα12/13. It could regulate changes in cytoskeletal rearrangement when cells are prepared to migrate. These changes depend on the activation of the Rho/Rock signaling pathway which directly modulates the myosin regulatory light chain (MLC). This phosphorylated protein is associated with the formation of small spherical outgrowths arising from the plasma membrane known as bubbles or blebs, in a process known as blebbing (Meshki et al. 2009).

     
  5. 5.
    Gαo. NK-1R activates Gαo in Sf9 cells (Nishimura et al. 1998). This subunit downstreams the GPCR Frizzled (Fz) signal. Gαo is crucial for the activation of Wnt-β-catenin signaling pathway (Malbon 2005).
    Neurokinin-1 Receptor, Fig. 2

    SP, after binding to the GPCR NK-1R, induces many cell signaling pathways

     

The Gβγ subunit activates effectors such as PLCβ, adenylyl cyclases, PI3K, K++ ion channels, and Src (Malbon 2005) (Fig. 2). β-arrestin is a member of the mitogen-activated protein kinase (MAPK) signaling pathway, and originally it was involved to mediate receptor uncoupling and internalization; however, it is currently known that β-arrestin is required for the activation of ERK1/2 by GPCRs. In the case of proteinase-activated receptor 2 (PAR2), β-arrestin forms a complex with the internalized receptor, Raf-1, and ERK1/2, retaining in the cytosol the activated kinases. This complex prevents the proliferative effects associated with the translocation of ERK1/2 into the nucleus, regulating the mitogenic potential of a given signal (DeFea et al. 2000). A different β-arrestin complex, containing the β2-adrenergic receptor (β2-AR) and the tyrosine kinase Src, also leads to the activation of ERK1/2 (Luttrell et al. 1999). The associations between trimeric G proteins and second messengers lead a cascade of intracellular events that cause a particular response, depending on the cell type.

Biological Actions of the NK-1R

  1. 1.

    Cell proliferation (Fig. 3). SP, after binding to the NK-1R expressed in glioma cells, induced mitogenesis and the incorporation of [3H]thymidine into the DNA and potently induced c-myc mRNA (Luo et al. 1996). Moreover, SP trough NK-1R activates MAPK cascade, including ERK1/2 and p38MAPK. These pathways are often activated under different conditions and can lead to both growth and apoptosis. The most commonly studied mechanism by which GPCRs activate MAPK is the release of G-protein βγ subunits which recruit components of the Ras-dependent cascade, such as SHC, GRB2, and Src, leading to the activation of Raf-1 and MAPK 1, a specific activator of ERK1/2 (Esteban et al. 2006). DAG activated by Gαq11 diffuses along the plasma membrane where it may activate a Ser/Thr PKC.

     
  2. 2.

    Cell migration (Fig. 3). This mechanism is regulated by neuropeptides/classical neurotransmitters (e.g., SP, noradrenaline, dopamine). Adrenoceptor, D2 receptor, or NK-1R antagonists inhibit the migration of tumor cells (Lang et al. 2004). SP, via the NK-1R, induces changes in cellular shape (e.g., melanoma or carcinoma cells), including blebbing, which is crucial in cell movement/spreading and in cancer cell infiltration (Meshki et al. 2009). Rho-associated protein kinase (Rock) is also involved in these changes, and, in glioma cells, it has been reported that SP induced the phosphorylation of p21-activated kinase (PAK) and an increased phosphorylation of the myosin regulatory light chain kinase (MLCK), but this was not observed in human non-tumor cells (Meshki et al. 2011).

     
  3. 3.

    Angiogenesis (Fig. 3). SP, after binding to the NK-1R located in endothelial cells, promoted angiogenesis (Ziche et al. 1990). Moreover, SP-induced calcium increase activates calcium PKC isoforms. PKC is involved but is not mandatory for VEGF induction. SP stimulates phosphorylation of both ERK and c-Jun N-terminal kinase (JNK MAP kinases), which can be activated by PKC-dependent and PKC-independent mechanisms. Activation of these MAPKs leads to activation of the AP-1 transcription factor, a heterodimer of c-Fos and c-Jun (Theoharides et al. 2010)

     
  4. 4.

    Antiapoptotic effect (Fig. 3). SP, via the NK-1R, stimulates cell proliferation and inhibits apoptosis by a mechanism involving the formation of a β-arrestin-dependent scaffolding complex that includes internalized NK-1R, Src, and the MAPK ERK1/2 (DeFea et al. 2000). The blockade of the NK-1R by NK-1R antagonist inhibited the basal kinase activity of Akt, increased apoptosis, and caused the cleavage of caspase-3 and the proteolysis of poly (ADP-ribose) polymerase. In the NK-1R-mediated Akt phosphorylation, it is known the total involvement of phosphatidylinositol 3-kinase (PI3K) and the non-receptor tyrosine kinase Src. the partial involvement of the epidermal growth factor receptor (EGFR), and the no involvement of MAPK/ERK (Akazawa et al. 2009).

     
  5. 5.

    Warburg effect (Fig. 3). SP, via the NK-1R, stimulates the breakdown of glycogen and increases the intracellular Ca2+ concentration, but this was completely blocked by the NK-1R antagonist CP-96,345 (Medrano et al. 1994). The Warburg effect occurs because most cancer cells predominantly produce energy by means of a high rate of glycolysis followed by lactic acid fermentation. Growing tumor cells typically have glycolytic rates up to 200 times higher than those of their normal tissues of origin; this occurs even if oxygen is plentiful. SP/NK-1R from tumor cells produces glycogen breakdown, and the glucose obtained increases the metabolism of these cells (Muñoz and Coveñas 2013).

     
  6. 6.

    Inflammation (Fig. 3). SP is a main mediator in neurogenic inflammation (O’Connor et al. 2004) and, via the NK-1R, triggers the activation of the transcription factor NF-κB that controls the expression of cytokines (Lieb et al. 1997). SP stimulates human peripheral blood monocytes to produce inflammatory cytokines, including interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)α (Lotz et al. 1988), and increases the release of TNFα and IL-10 by human macrophages and monocytes (Ho et al. 1996).

     

NK-1R as a Therapeutic Target and NK-1R Antagonists as New Drugs

There are two types of NK-1R antagonists: peptide NK-1R antagonists and non-peptide NK-1R antagonists. They are a heterogeneous group of compounds that, after binding specifically to the NK-1R, block the pathophysiological actions mediated by SP. Peptide NK-1R antagonists (L-amino acids are replaced by D-amino acids in the SP molecule) are also known as SP analogue antagonists. They are rapidly degraded by peptidases, exert toxic effects, and are not brain penetrant. Non-peptide NK-1R antagonists include many compounds with different chemical compositions but showing similar stereochemical features (the affinity for the NK-1R); they are not degraded by peptidases and are brain penetrant (Muñoz and Coveñas 2013). To date, two non-peptide NK-1R antagonists are used in clinical practice: aprepitant (Emend) and its intravenous administered prodrug fosaprepitant (Ivemend). They are used for the treatment of nausea and vomiting. Non-peptide NK-1R antagonists and SP bind to different sites of the NK-1R: the peptide binds to the extracellular ends of the transmembrane helices, and the antagonists bind more deeply between the III-VII transmembrane domains (Muñoz and Coveñas 2013) (Fig. 1).
Neurokinin-1 Receptor, Fig. 3

By triggering many cell signaling pathways, the NK-1R regulates several biological functions: inflammation, cell proliferation, angiogenesis, and cell migration

The SP/NK-1R System: Clinical Significance

  1. 1.

    This system is involved in chemotherapy-induced nausea and vomiting (CINV). NK-1R antagonists improve CINV (Hesketh et al. 1999).

     
  2. 2.

    Pruritus. A novel antipruritic strategy has been reported by targeting the NK-1R with aprepitant (Ständer et al. 2010).

     
  3. 3.

    Antidepressant. In the limbic system, the SP/NK-1R system is involved in depression. Aprepitant showed the same antidepressant activity as paroxetine, and the side effects exerted by this non-peptide NK-1R antagonist were similar to placebo (Kramer et al. 1998).

     
  4. 4.

    Viral infection. The SP/NK-1R system is involved in viral fusion and transcription (e.g., HIV, viral myocarditis), whereas NK-1R antagonists exerted an antiviral action (Wang et al. 2007; Robinson et al. 2009). In a clinical assay, these antagonists improved the biological biomarkers, and it has been suggested that increased doses of NK-1R antagonists could exert higher antiviral effects against HIV (Barrett et al. 2016).

     
  5. 5.

    Inflammatory diseases. The SP/NK-1R system is involved in neurogenic inflammation, and NK-1R antagonists exert anti-inflammatory effects (O’Connor et al. 2004; Muñoz and Coveñas 2014).

     
  6. 6.

    Cancer progression. The SP/NK-1R system promotes cancer progression. SP induces tumor cell proliferation, has an antiapoptotic effect, stimulates angiogenesis, and induces tumor cell migration for invasion and metastasis. NK-1R antagonists counteract all aforementioned mechanisms (Muñoz and Coveñas 2013).

     

Summary

The NK-1R belongs to the GPCRs family, and it is widely distributed by the body, including cancer cells (in which it is overexpressed). The preferred endogenous ligands for the NK-1R are SP and HK-1. The tr-NK-1R is overexpressed in cancer cells and in tumors induced by inflammatory processes. SP, via the NK-1R, regulates many cell signaling pathways involved in inflammation, mitogenesis, glycogen breakdown, antiapoptotic effect, angiogenesis, and cell migration. The NK-1R is also involved in many pathophysiological actions: nausea and vomiting, pruritus, viral infection, inflammation, and cancer progression. NK-1R antagonists can counteract these pathophysiological actions exerting antiemetic, antipruritic, antiviral, anti-inflammatory, and antitumor effects. The NK-1R could be considered a new and promising target in many diseases, and non-peptide NK-1R antagonists could be used for numerous therapeutic interventions.

Notes

Acknowledgments

The authors wish to thank Mr. Javier Muñoz (University of Seville, Spain) for technical assistance.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Research Laboratory on Neuropeptides (IBIS)Virgen del Rocío University HospitalSevilleSpain
  2. 2.Laboratory of Neuroanatomy of the Peptidergic Systems, Institute of Neurosciences of Castilla y León (INCYL)University of SalamancaSalamancaSpain
  3. 3.Unidad de Cuidados Intensivos PediátricosVirgen del Rocío University HospitalSevilleSpain