BioMed Research International

BioMed Research International / 2015 / Article
Special Issue

Chemotherapy-Induced Nausea and Vomiting

View this Special Issue

Review Article | Open Access

Volume 2015 |Article ID 495704 | 14 pages | https://doi.org/10.1155/2015/495704

Biological and Pharmacological Aspects of the NK1-Receptor

Academic Editor: Bernardo L. Rapoport
Received23 Dec 2014
Revised19 Apr 2015
Accepted25 Apr 2015
Published03 Sep 2015

Abstract

The neurokinin 1 receptor (NK-1R) is the main receptor for the tachykinin family of peptides. Substance P (SP) is the major mammalian ligand and the one with the highest affinity. SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, and cell survival. It is also considered a mitogen, and it has been associated with tumorigenesis and metastasis. Tachykinins and their receptors are widely expressed in various human systems such as the nervous, cardiovascular, genitourinary, and immune system. Particularly, NK-1R is found in the nervous system and in peripheral tissues and are involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis and to sensory neuronal transmission associated with depression, stress, anxiety, and emesis. NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and the area postrema). This anatomical localization has led to the successful clinical development of antagonists against NK-1R in the treatment of chemotherapy-induced nausea and vomiting (CINV). The first of these antagonists, aprepitant (oral administration) and fosaprepitant (intravenous administration), are prescribed for high and moderate emesis.

1. Tachykinins and Their Receptors

The tachykinins are one of the largest conserved families of peptides involved in neurotransmission and inflammatory processes. The idea that tachykinins act exclusively as neuropeptides is currently being challenged. Substance P (SP), a small undecapeptide present in both mammalian and nonmammalian species, was the first member of the family to be discovered (as early as 1931, by von Euler and Gaddum). SP is associated with multiple processes: hematopoiesis, wound healing, microvasculature permeability, neurogenic inflammation, leukocyte trafficking, cell survival, and metastatic dissemination [15]. The three classical members of the mammalian tachykinin family are SP and neurokinin A (NKA), both encoded by the TAC1 gene, and neurokinin B (NKB), encoded by the TAC3 gene. A third mammalian tachykinin gene (TAC4) codes for hemokinins and endokinins [1, 6, 7]. The TAC1 gene (according to the Human Genome Organization (HUGO) Gene Nomenclature Committee (http://www.genenames.org/) also encodes other tachykinins, including NKA, neuropeptide K (NPK). and neuropeptide γ (NPγ). On the other hand, the TAC3 gene only codes for NKB (previously known as PPT-B gene). In 2000, Zhang et al. identified a third gene called TAC4 (previously named preprotachykinin-C (PPT-C)) and demonstrated its association with the hematopoietic system and the maturation of B lymphocytes [7]. This gene encodes hemokinin 1 (HK-1) and its shorter derivative hemokinin (4–11) and four other peptides called endokinins (EKS), EKA, EKB, EKC, and EKD [6].

Tachykinin receptors have been divided into three different types according to their affinity ligands (high or low): TACR1 (NK-1 receptor), TACR2 (NK-2 receptor), and TACR3 (NK-3 receptor) (Table 1), which have preferential (but not exclusive) affinities for SP, NKA, and NKB respectively [810]. The order of potency of these receptors per tachykinin is shown as follows [10, 11]. Order of affinity of tachykinin receptor by its agonists is(a)Receptor NK-1: SP>NKA>NKB;(b)Receptor NK-2: NKA>NKB>SP;(c)Receptor NK-3: NKB>NKA>SP.


ReceptorGenAccess numberChromosomal location

NK-1TACR1NM_0010582p13.1-p12
NK-2TACR2NM_00105710q11-q21
NK-3TACR3NM_0010594q25

NPγ and NPK preferentially bind to the NK-2 receptor. The affinities of NKA and NKB for the NK-1 receptor are, respectively, 100 and 500 times lower than that of SP [12]. It has also been reported that SP interacts with fibronectin (FN) and hematopoietic growth factor inducible neurokinin-1 type (HGFIN) [13, 14]. The homology between the NK1 receptor and HGFIN has recently been described. This finding may be relevant because both the NK-1 receptor and HGFIN have been linked to tumorigenesis, including breast cancer (BC) [14]. However, whereas the NK-1 receptor has been described as a tumor promoter, HGFIN may act as a suppressor [14].

The three tachykinin receptors belong to family 1 (rhodopsin-like) G protein-coupled receptors (GPCRs) and are encoded by five exons [9, 15]. These are seven-transmembrane-helix receptors which share the same structural unit: three extracellular (EL1, EL2, and EL3) and three intracellular loops (C1, C2, and C3) with the possibility of a fourth loop, due to the palmitoylation of cysteine (Cys), flanked by seven intermembrane domains (TM 1-VII), and an amino-terminal extracellular and carboxy-terminal cytoplasmic domain [9] (Figure 1).

The carboxy-terminal conserved domain of tachykinins (Phe-X-Gly-Leu-Met-NH2) interacts with tachykinin receptors, while the amino-terminal sequence is responsible for the specificity of the receptor [16]. All tachykinins are amidated at the C-terminal and deamidation suppresses their activity [8]. The second and third loops are involved in the binding of agonists or antagonists, while the third cytoplasmic loop is responsible for binding to protein G. The C-terminus contains serine/threonine residues which, once phosphorylated, cause desensitization of the receptor when it is repeatedly activated by the agonist. The 5′ region of the gene has several putative regulatory DNA elements such as the cAMP responsive element, AP-1, AP-2, AP4, NF-кB, OCT-2, and a domain Sp-1 [16]. Specifically, the NK-1 receptor has 407 amino acids and a relative molecular mass of 46 kDa [17]. NK-2 and NK-3 consist of 398 and 465 amino acids, respectively, NK-3 being the longest of the three receptors. The most important splicing identified loses the last 96 amino acids at the C-terminus and thus has 311 amino acids [1820] (Figure 1). This shorter or truncated isoform (NK1-Tr) is generated when the intron located between exons 4 and 5 is not removed and the premature stop codon is identified before starting exon 5.

Lai et al. [21] observed that SP specifically increased intracellular calcium in embryonic kidney cells (HEK293) stably transfected with the long isoform, while there was no effect in those transfected with the truncated isoform. Likewise, cells expressing the long isoform activated NF-B and IL-8, while those expressing the truncated one had a lower mRNA expression of IL-8 and were unable to activate NF-кB. The activation of protein kinase Erk was also altered in the same cells: whereas phosphorylation of this protein through the long isoform was fast (1 to 2 minutes) and sustained, cells transfected with truncated isoform were not able to phosphorylate Erk protein within 20 min after exposure to SP [21]. In addition, other studies have demonstrated that SP had a lower relative affinity for the truncated receptor form (up to 10 times less than the full isoform) [18]. Moreover, 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 [2224].

Therefore, the truncated form should be capable of prolonging the responses after ligand binding because its desensitization and internalization are affected. Besides the differences between the two isoforms, another important phenomenon involved in the receptor signaling should be mentioned. Tansky, Leeman, and Pothoulakis showed that the amino terminal end had two glycosylated Asn (N-) sites and described how these glycosylations can influence the functional level of the receptors [25].

They observed that nonglycosylated receptors showed half the affinity for SP shown by glycosylated receptors, and in fact the nonglycosylated NK-1 receptor was internalized faster than the glycosylated form. This also suggested the possibility that glycosylation may be a feature in the stabilization of the receptor in the plasma membrane. Several bands of different molecular weights have been identified, probably due to this phenomenon. For example, in lymphocytes, certain forms of glycosylated receptor (58 kDa) have been described [26], while others with bands of 38 and 33 kDa appear in IM-9 lymphoblasts (26). Furthermore, isoforms with bands of 75, 58, 46, and 34 kDa have been identified in several studies of tumor pancreatic carcinoma cell lines [27, 28].

In the past two decades, other isoforms have been identified besides the conventional ones, with different SP affinities. For example, in rat salivary glands another apparently truncated isoform has also been detected in the C-terminal end, with 8 kDa less than the long isoform [29]. Li et al. also demonstrated that the short isoform seems to have an SP affinity similar to that of the complete isoform. It has been suggested that this isoform comes from posttranslational modifications [30]. In addition, other studies have shown that some receptor isoforms present different affinities from the “classic” forms. This has led to a division of the NK-1 receptor into three different classes: (1) the “classic” NK-1 receptor (which shows greater binding affinity for the SP ligand), (2) the “sensitive to septide” NK-1 receptor (showing a very similar affinity for binding to SP and other tachykinins as NKA, NPK, NPγ, NKB, and even other synthetic peptides such as septide fragment 6–11 SP, which gives the receptor its name) [10, 31], and (3) the “new NK-1 sensitive” receptor [32]. This subtype has a higher affinity for longer tachykinins and does not bind to septide or SP (6–11). However, more studies are needed to identify the real differences in the signaling pathways of each NK-1R isoform and the preferred sites of expression of the different isoforms or glycosylated forms.

1.1. Signaling Pathways Modulated by Tachykinins and Their NK-1R

The physiological processes mediated by SP or other tachykinins occur via the NK-1 receptor, which belongs to the large family of G-protein-coupled receptors (GPCRs). Via second messengers, G proteins activate transduction pathways within the cell. Which pathways are activated by G proteins depends on the nature of the proteins belonging to this large family: for example, the activation of NF-κB mediated by SP, interleukins, or growth factors (IL-1, IL-6, IL-8, TNF-α, and IFNy) and the activation of MAPKs pathway or PI3K/Akt among others [3335].

1.1.1. GPCR-Mediated Signal Transduction: Classification and Function of G Proteins

GPCRs mediate their signaling through heterotrimeric G proteins transmitting signals from a variety of surface cell receptors to enzymes and ion channels. This complex is composed by three distinct subunits: the Gα subunit that binds to GDP/GTP and the Gβ and Gγ subunits that form the Gβγ complex (which present strong bindings between them) [36, 37]. After binding SP to the specific NK-1 receptor, a change occurs in the Gα subunit, allowing it to exchange GTP for GDP and permitting the dissociation of the Gβγ dimer. These subunits (Gα and Gβγ) begin their own signaling cascade separately and positively or negatively regulate the activity of enzyme effectors and ion channels that are cell type- or GPCR-specific [38, 39].

The GTP hydrolysis returns the Gα subunit to its inactive state, allowing again the trimeric formation with the Gβγ subunit [40]. Gβγ in contrast to the Gβγ subunit, the broad range of the α subunit is limited because all α subunits, except , have a palmitic acid posttranslational modification in the amino-terminal portion, which keeps them adhered to the plasma membrane [41]. The α subunit itself has intrinsic GTPase capacity and may modulate its own inactivation. In any case, this GTP hydrolysis is relatively low compared with other accessory proteins called cytoplasmic regulators of G protein signaling (RGS) [42] (Figure 2).(i): the receptor interaction by the agonists regulates the activation of protein and the subsequent activation of phospholipase Cβ (PLCβ), which degrades the phosphatidylinositol 4, 5-bisphosphate (PIP2) to produce two compounds: diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3), responsible for increasing intracellular calcium [4347].(ii): this subunit is responsible for the activation of the second messenger adenylate cyclase (AC), which catalyzes the conversion of cytoplasmic ATP into cyclic adenosine monophosphate (cAMP) when the Gs-related pathway is activated (by contrast, AC inhibition is conducted by the Pertussis toxin-sensitive -protein (PTX) in rat submandibular cells) [48]. Other studies have reported that the Gs subunit is the substrate of cholera toxin (CTX), produced by Vibrio cholerae, which catalyzes its ADP ribosylation and inhibits its intrinsic GTPase activity [42]. It has been widely reported that increased cAMP levels lead to activation of protein kinase A (PKA). Activation of PKA, then, phosphorylates the transcription factor CREB (cAMP-responsive element-binding protein CRE). CREB binds to the cAMP response element (CRE) of a target gene and negatively affects the activation of NF-кB [49]. However, despite the Gs action, the power to generate cAMP accumulation by NK-1R agonists is lower than the ability to induce IP3 and intracellular calcium of [50].(iii): the role of this class member is to mediate the inhibition of different types of AC. Functional studies have been conducted with PTX, produced by Bordetella pertussis. Unlike CTX, PTX decouples the G protein from its receptor and remains inactive and bound to GDP [51].(iv)G12/13: this subunit is expressed ubiquitously in mammals and is composed by two proteins, Gα12 and Gα13 which are also toxin resistant [42]. Meshki et al. reported that the G12/13 subunit could regulate changes in cytoskeletal rearrangement when the cell was preparing to migrate. These changes depend on the activation of Rho/Rock which directly modulates the myosin regulatory light chain. Phosphorylation of this protein is associated with the formation of small spherical outgrowths arising from the membrane known as bubbles or blebs, in a process known as blebbing. This process is not always associated with apoptosis but may be associated with the cytoplasmic disorganization at the time of cell migration and Meshki et al.’s study showed how the NK-1 receptor had the ability to interact with the G12/13 protein throughout this process [52].(v): this subunit is one of the most abundant G proteins in neuronal and neuroendocrine tissues [53]. Nishimura et al. provided the first evidence of NK-1R’s potential to activate in Sf9 cells [54]. This subunit signals downstream of frizzled (Fz) GPCRs. is crucial for the activation of Wnt-β-catenin signaling pathways [42]. While is abundant in nervous tissues, its deficiency causes lesions that appear to be mediated mainly by this subunit [42, 55].The Gβγ subunit has been less studied than Gα. The βγ complex can be formed by five different β subunits and 12 γ subunits [42]. At first, it was thought that its role was merely passive but later it was found that it may play a role in the activation of effectors such as PLCβ, adenylyl cyclases, PI3K, K+ ion channels, and Src. All these associations between trimeric G proteins and second messengers lead to a cascade of intracellular events that cause a particular response, depending on cell type.

GPCRs constitute a large family of cell surface receptors which regulate many cellular functions, including cell proliferation, survival and motility, the sense of smell, emesis, and depression. They have recently emerged as key receptors in tumor growth, angiogenesis, and metastasis.

Specifically, interactions involving the protein occur in several systems and endocrine secretion, vasodilatation, neuromodulation, and activation of monocytes as well as in cell proliferation [5660]. Therefore, experimental evidence from several recent studies supports the view that alterations in the endocrine system regulated by NK-1R and SP contribute to the development of pathologies such as depression, neural degeneration, alcohol addiction, pain, migraine, inflammatory bowel disease, pruritus, viral infection, bacterial infection, cancer, and emesis [27, 35, 6165].

1.1.2. Signaling Pathways of NK-1R and SP

The NK-1 receptor signals through different pathways depending on the nature of the G proteins. For example, in glioblastoma cell lines and in many other tumor types, the SP binding causes the accumulation of DAG, which in turn activates PKC. This protein phosphorylates other proteins such as c-Raf-1 and MEK, which phosphorylate tyrosine protein kinase Erk1/Erk2 (also known as p-42/44) of the MAPK protein family [27, 6569]. The mechanism by which PKC activates ERK is not entirely understood. Discordant results are found in the literature, in which different molecules have been implicated in MAPK activation via GPCRs. These disparities may be explained by differences in the cell culture methods used or the nature of the samples analyzed [7076]. Subsequently, transcription factors such as c-fos or c-myc are activated and induce DNA synthesis and cell proliferation (Figure 3). Another protein kinase activated by NK-1 receptor is PKCδ. Earlier studies by Della Rocca et al. [77] found that PLC activation dependent on both (α1B adrenergic receptor) and Gβγ subunits (Gi dissociated from α2A adrenergic receptor protein) increased cytoplasmic IP3 levels, resulting in an increase in cytoplasmic Ca2+. High concentrations of intracellular calcium, probably through calmodulin, lead to kinase activation, called proline-rich tyrosine kinase 2 (Pyk2, English protein tyrosine kinase 2) associated with focal adhesion kinase (FAK). In turn, this Pyk2 activity (now known as PTK2B) regulates kinase protein Src. Src-dependent tyrosine phosphorylation of adaptor proteins such as Shc recruits Grb2-SOS complex to the plasma membrane and initiates the phosphorylation cascade leading the Erk1/2 activation that triggers cell proliferation pathways [77].

According to some studies, MAPK activation depends not only on G proteins and their canonical or classical pathway signaling, but also on the scaffold for the assembly of multiprotein complexes for NK-1R internalization or other GPCRs. In some models such as Gαq-coupled proteinase-activated receptor 2 (PAR2), the interaction of this receptor with β-arrestin internalization proteins causes a retention of Raf-1 and phosphorylated Erk1/2 proteins in the cytoplasm and these proteins cannot be transferred to the nucleus [78].

However, others such as the β2-adrenergic receptor (β2-AR) are internalized through the complex formed by β-arrestin, Src, and Erk [79]. In this case, β2-AR receptor activation causes Erk1/2 phosphorylation and induces a different set of cellular responses to those produced by PAR2, since Erk1/2 is not retained in the cytoplasm. These differences may be due to the different scaffolding protein complexes responsible for the distinct subcellular localization of activated kinases for internalization, because they may be responsible for governing the mitogenic potential of each particular signal.

The requirement for β-arrestin-dependent endocytosis differs between receptor types. This variation also appears to be cell type-independent, as the two receptors (NK-1R and PAR2) expressed in the same cell line (KNRK) induce the formation of different protein scaffold complexes [22]. Therefore, better studies are needed to identify the GPCR C-terminal end responsible for the internalization process, since this cytoplasmic tail is the key for binding proteins. Feng et al. [23] observed that stimulation of the NK-1 receptor (overexpressed in KNRK cells or naturally expressed in endothelial cells) by SP, activated Erk1/2 via a β-arrestin-dependent mechanism. SP induced the formation of a multiprotein complex near the plasma membrane containing β-arrestins, Src, and Erk1/2. Once activated, Erk1/2 translocates into the nucleus to induce proliferation and antiapoptotic effects [22].

NK-IR internalization and recycling seems to modulate cellular responses to SP binding, and although SP is degraded, the receptor recovery towards the plasma membrane does not seem to be dependent on new protein synthesis [80].

In addition to its mitogenic activity, SP is also capable of stimulating cytokine release from normal cells and immune cells from the tumor microenvironment in order to promote tumor progression. Moreover, the NF-кB-mediated G protein is involved in several cell types. It has been shown that tachykinins activate NF-кB and stimulate the production of proinflammatory cytokines in several cell types: colon epithelial cells [34], macrophages [81], mast cells [82], T cells [83], and astrocytoma cells [84] and in a lung adenocarcinoma epithelial cell (A549) [56]. However, not all the mechanisms by which this activation occurs are totally known. NF-кB activation by SP is calcium-dependent in astrocytoma cells, but not in colon epithelial cells [34, 81].

Another downstream effector of the various signaling pathways activated by NK-1R is the serine/threonine protein kinase Akt, also known as kinase B (PKB) protein. Phosphoinositol 3-kinase or PI3K is responsible for activating Akt. PI3K can be activated by receptor tyrosine kinases (RTKs) or by integrins transactivation or GPCRs [85]. It is unclear how G proteins activate PI3K, but it is known that PIP2 is converted to PIP3 (capable of activating Akt) by PI3K, whereas PTEN opposes this reaction by dephosphorylating PIP3. The role of Gβγ subunit in PI3K activation has also been reported, because it is known that there is a direct activation of kinase by the βγ dimer [85] (Figure 3). González Moles and colleagues [86] reported that stimulation of the bradykinin receptor (a receptor of the same family as NK-1) by Gαq and β1γ2 subunits increased Akt phosphorylation due to PI3K and this was responsible for NF-кB activation in HeLa transfected cells. These results suggested that if bradykinin receptor phosphorylation leads to IKK2 activation, then activation of Gαq, β1γ2, PI3K and Akt is required (Figure 3). However, these authors reported that inhibition of PI3K and Akt only partially inhibited the activation of downstream proteins, so their study does not exclude other parallel signaling pathways such as those mentioned above, including the MAPK pathway.

Finally, other intracellular signaling mechanisms by which NK-1R is responsible for SP-induced cell shape changes have also been described. These changes depend on the activation of Rho/Rock which directly modulates the myosin regulatory light chain. Meshki and collaborators reported that NK1R has the ability to interact with proteins from the G12/13 family [52].

Therefore, all these studies have identified key molecules involved in NK-1R signaling, in various cell types, such as p42/44 protein (MAPK), p38 MAPK, NFкB, PI3K, Akt, Src, EGFR, Rho/Rock, β-arrestin, and Pyk2 depicted in Figure 3.

2. Distribution of Tachykinin Receptors in the Body

As previously mentioned, tachykinins and their receptors are widely expressed in various human systems such as the nervous [19, 8789], cardiovascular [9093], genitourinary [94], immune systems, gastrointestinal tract [28, 95102] and in some tissues such as salivary gland [103], skin, and muscle (Figure 4). Tachykinin receptors are not evenly distributed. The NK-1 and NK-3 receptors are found in the nervous system and in peripheral tissues, whereas the NK-2 receptor is found only in the peripheral tissues (kidney [104], lung, placenta [105] and skeletal muscle) [57, 106, 107]. Specifically, like its higher affinity ligand SP, the NK-1 receptor is involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation and modulation of cell proliferation. It also acts as a neuromodulator contributing to brain homeostasis but also the sensory neuronal transmission associated with depression, stress, anxiety and emesis. Additionally, the NK-1 receptor is responsible for modulating the immune system’s inflammatory response. Expression of the NK-1 receptor has been identified in lymphocytes, monocytes, macrophages, NK cells and microglia. NK-1R is also expressed in bone marrow cells (cells of lymphoid and myeloid lineage) and is considered an hematopoietic regulator [58, 108112]. Both in normal tissue and during hematopoiesis, NK-1R mediates stimulation effects and NK-2 exerts suppressor functions (when NK-1R is expressed in normal cells, there is a down-regulation of NK-2R) [113, 114].

3. NK-1R as a Therapeutic Target

SP, through the NK-1 receptor signal, has been implicated in the regulation of many physiological and pathophysiological functions such as neuronal survival, regulation of cell movement, pain, inflammation, salivation, depression, stress responses, emotions, reward, neurogenesis, vigilance, cancer progression, and emesis [63, 115123]. Moreover, the tachykinergic system can regulate motility in several cells [52], stimulates platelet aggregation [124], and is present in many human body fluids such as breast milk, blood, saliva, and cerebrospinal fluid [122]. The ubiquity of the SP/NK-1 receptor system in many biological functions and its upregulation under pathological conditions makes this system an important target for several diseases (depression, neural degeneration, alcohol addiction, pain, migraine, inflammatory bowel disease, pruritus, viral infection, bacterial infection, cancer, and emesis [27, 35, 6165]). Among all these conditions, the NK-1R antagonist has only been subject to clinical development in the treatment of chemotherapy-induced nausea and vomiting (CINV) and in depression. These clinical trials led to the registration of aprepitant by the regulatory agencies EMA and FDA as the first NK-1 receptor antagonist to treat chemotherapy-induced nausea and vomiting.

3.1. Emesis

NK-1R and SP are present in brain regions involved in the vomiting reflex (the nucleus tractus solitarius and area postrema) [125]. Aprepitant (MK-869, brand name EMEND) is the first the neurokinin-1 receptor antagonist to be commercialized. When added to a standard regimen of a 5-HT3 receptor antagonist and dexamethasone in cancer patients receiving highly emetogenic chemotherapy, aprepitant improves the complete response (CR) rate in acute CINV. It also improves the CR in delayed CINV when used in combination with dexamethasone compared with dexamethasone alone [126]. The use of aprepitant in patients receiving moderately emetogenic chemotherapy was recently approved after phase III clinical trials had demonstrated its efficacy [127]. Aprepitant is a substrate, a moderate inhibitor, and an inducer of cytochrome P450 (CYP3A4) and CYP2C9. Drug interactions should be monitored when aprepitant is given together with agents affected by CYP3A4 and CYP2C9 isoenzymes.

Aprepitant is the only antagonist with high affinity for the NK-1 receptor approved to date by the US Food and Drug Administration (FDA). It was approved in 2003 for oral administration. In 2008, its prodrug, fosaprepitant, was approved for intravenous use.

These two drugs are the only available agents in this class for preventing chemotherapy-induced and postoperative nausea and vomiting. However, other agents such as netupitant and rolapitant are currently undergoing phase III clinical trials and are expected to be commercialized in the near future [128]. More information on NK-1R as a target for CINV will appear in the following pages of this issue.

3.2. Depression

The NK-1R antagonist was tested as a novel antidepressant mechanism in an exploratory phase II clinical trial also using aprepitant [121].

In situations of stress and anxiety, neuropeptides such as SP are released at a rate proportional to the intensity and frequency of stimulation [129]. In fact some studies show that the SP/NK-1R interaction plays an important role in the regulation of emotional behavior [129]. There is evidence that psychosocial help reduces depression, anxiety, and pain and may prolong survival in some cancer patients. Indeed, various forms of stress have been associated with mammary tumorigenesis [130, 131]. Specifically, the NK-1 receptor and SP are involved in emotional responses to stress, suggesting that an alteration in the tachykinergic system may be the key to triggering pathogenesis such as depression (SP expression has been shown to increase during depression [121] whereas the genetic deletion of its receptor induces an anxiolytic and antidepressant effect [132]). It has even been reported that psychotropic drugs modify the expression of genes encoding the synthesis of tachykinin in some areas of the rat brain [133, 134]. Some of these findings suggest that a reduction in SP levels in certain regions of the brain, with NK-1R antagonists, may have a therapeutic effect as antidepressant drug in affective disorders and also in disorders related to cancer. In fact, several publications and reviews have reported experiments correlating emotional behavior (the limbic system) and cancer [35, 135, 136].

3.3. Cancer

Experimental evidence obtained in recent years supports the idea that alterations in the neuroendocrine system may contribute significantly to the tumorigenic process. The tachykinins act directly on tumor cells, modulating their responses in terms of proliferation and survival but also contribute indirectly by altering the tumor microenvironment and processes related to tumor progression. SP and its receptor are expressed in a wide variety of tumor cell lines (WERI-Rb-1 and Y-79 from retinoblastoma, U373 MG and GAMG from glioma, SNK-BE(2), Kelly and IMR-32 from neuroblastoma, CAPAN-1 and PA-TU 8902 from pancreatic cancer, Hep-2 from laryngeal cancer, 23132/87 from gastric cancer, and SW-403 from colon cancer) [65, 67, 137] and tumors such as astrocytomas, gliomas, neuroblastomas, pancreatic cancer, melanomas, and breast cancer [28, 86, 123, 135, 138, 139].

It has been estimated that the NK-1R antagonist aprepitant is 45000 times more selective than for the NK-2 receptor and more than 3000 times more selective for the NK-1 receptor than for the NK-3 receptor [140]. This compound has shown antiproliferative properties in tumoral cell lines of glioma, neuroblastoma, retinoblastoma, pancreas, larynx, colon, and gastric carcinoma [62, 64, 141, 142]. A clinical trial for moderate to severe depression, at a dose of 300 mg/day, found this compound to be safe and well tolerated. No statistically significant differences were found comparing adverse events with patients treated with placebo [121]. Although no clinical trials have yet been initiated, there are sufficient preclinical data to believe that NK-1R antagonists may one day be assessed as anticancer agents [3, 5, 28, 35, 62, 64, 122, 123, 137, 138, 141148].

4. Conclusion

The NK-1 receptor is the high affinity receptor of SP, the major mammalial tachykinin. It belongs to the G protein-coupled receptors (GPCRs) family. Tachykinins and their receptors are widely expressed in various human systems. NK-1 receptors are found in the nervous system and in peripheral tissues. Specifically, the NK-1 receptor is involved in cellular responses such as pain transmission, endocrine and paracrine secretion, vasodilation, and modulation of cell proliferation. Also it acts as a neuromodulator contributing to brain homeostasis and sensory neuronal transmission associated with depression, stress, anxiety, and emesis.

NK-1R and SP are present in brain regions involved in the vomiting reflex (nucleus tractus solitarius and in the area postrema). This anatomical localization has led to the successful clinical development of antagonist against NK-1R in the treatment of CINV. Aprepitant is the first NK1R antagonist of this new antiemetic family. Two other NK-1R antagonists have finished clinical trials and it is expected that they will be commercialized in the near future.

Conflict of Interests

The authors have no potential conflict of interests to declare.

Acknowledgments

This work has been partially funded by a grant from the Fondo de Investigación Sanitaria, Instituto de Salud Carlos III (PI12/01706), by a grant from the Fundación Cellex and by Redes Temáticas de Investigación en Cáncer (RTICC, RD12/0036/0055) (http://www.rticc.org/). This study was supported by grants from the Fondo de Investigación Sanitaria (PI08022), Instituto de Salud Carlos III-Subdireción General de Evaluación y Fomento de Investigación, Fondo Europeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa, the Fundación Cellex, and Redes Temáticas de Investigación en Cáncer (RTICC, RD07/0020/2014).

References

  1. C. Palma, “Tachykinins and their receptors in human malignancies,” Current Drug Targets, vol. 7, no. 8, pp. 1043–1052, 2006. View at: Publisher Site | Google Scholar
  2. R. G. Murthy, B. Y. Reddy, J. E. Ruggiero, and P. Rameshwar, “Tachykinins and hematopoietic stem cell functions: implications in clinical disorders and tissue regeneration,” Frontiers in Bioscience, vol. 12, no. 12, pp. 4779–4787, 2007. View at: Publisher Site | Google Scholar
  3. C. Mayordomo, S. García-Recio, E. Ametller et al., “Targeting of substance P induces cancer cell death and decreases the steady state of EGFR and Her2,” Journal of Cellular Physiology, vol. 227, no. 4, pp. 1358–1366, 2012. View at: Publisher Site | Google Scholar
  4. H. S. Hong, J. Lee, E. Lee et al., “A new role of substance P as an injury-inducible messenger for mobilization of CD29+ stromal-like cells,” Nature Medicine, vol. 15, no. 4, pp. 425–435, 2009. View at: Publisher Site | Google Scholar
  5. D. Singh, D. D. Joshi, M. Hameed et al., “Increased expression of preprotachykinin-I and neurokinin receptors in human breast cancer cells: implications for bone marrow metastasis,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 1, pp. 388–393, 2000. View at: Publisher Site | Google Scholar
  6. R. Patacchini, A. Lecci, P. Holzer, and C. A. Maggi, “Newly discovered tachykinins raise new questions about their peripheral roles and the tachykinin nomenclature,” Trends in Pharmacological Sciences, vol. 25, no. 1, pp. 1–3, 2004. View at: Publisher Site | Google Scholar
  7. Y. Zhang, L. Lu, C. Furlonger, G. E. Wu, and C. J. Paige, “Hemokinin is a hematopoietic-specific tachykinin that regulates B lymphopoiesis,” Nature Immunology, vol. 1, no. 5, pp. 392–397, 2000. View at: Publisher Site | Google Scholar
  8. T. Werge, “The tachykinin tale: molecular recognition in a historical perspective,” Journal of Molecular Recognition, vol. 20, no. 3, pp. 145–153, 2007. View at: Publisher Site | Google Scholar
  9. J. N. Pennefather, A. Lecci, M. L. Candenas, E. Patak, F. M. Pinto, and C. A. Maggi, “Tachykinins and tachykinin receptors: a growing family,” Life Sciences, vol. 74, no. 12, pp. 1445–1463, 2004. View at: Publisher Site | Google Scholar
  10. N. M. Page, “New challenges in the study of the mammalian tachykinins,” Peptides, vol. 26, no. 8, pp. 1356–1368, 2005. View at: Publisher Site | Google Scholar
  11. N. M. Page, “Brain tachykinins,” in The Handbook of Biologically Active Peptides, chapter 105, Elservier, 1st edition, 2006. View at: Google Scholar
  12. N. P. Gerard, L. A. Garraway, R. L. Eddy Jr. et al., “Human substance P receptor (NK-1): organization of the gene, chromosome localization, and functional expression of cDNA clones,” Biochemistry, vol. 30, no. 44, pp. 10640–10646, 1991. View at: Publisher Site | Google Scholar
  13. R. L. Metz, P. S. Patel, M. Hameed, M. Bryan, and P. Rameshwar, “Role of human HGFIN/nmb in breast cancer,” Breast Cancer Research, vol. 9, no. 5, article R58, 2007. View at: Publisher Site | Google Scholar
  14. P. Rameshwar, “Implication of possible therapies targeted for the tachykinergic system with the biology of neurokinin receptors and emerging related proteins,” Recent Patents on CNS Drug Discovery, vol. 2, no. 1, pp. 79–84, 2007. View at: Publisher Site | Google Scholar
  15. C. A. Maggi, “The mammalian tachykinin receptors,” General Pharmacology, vol. 26, no. 5, pp. 911–944, 1995. View at: Publisher Site | Google Scholar
  16. T. M. O'Connor, J. O'Connell, D. I. O'Brien, T. Goode, C. P. Bredin, and F. Shanahan, “The role of substance P in inflammatory disease,” Journal of Cellular Physiology, vol. 201, no. 2, pp. 167–180, 2004. View at: Publisher Site | Google Scholar
  17. B. Hopkins, S. J. Powell, P. Danks, I. Briggs, and A. Graham, “Isolation and characterisation of the human lung NK-1 receptor cDNA,” Biochemical and Biophysical Research Communications, vol. 180, no. 2, pp. 1110–1117, 1991. View at: Publisher Site | Google Scholar
  18. T. M. Fong, S. A. Anderson, H. Yu, R.-R. C. Huang, and C. D. Strader, “Differential activation of intracellular effector by two isoforms of human neurokinin-1 receptor,” Molecular Pharmacology, vol. 41, no. 1, pp. 24–30, 1992. View at: Google Scholar
  19. P. W. Mantyh, S. D. Rogers, J. R. Ghilardi, J. E. Maggio, C. R. Mantyh, and S. R. Vigna, “Differential expression of two isoforms of the neurokinin-1 (substance P) receptor in vivo,” Brain Research, vol. 719, no. 1-2, pp. 8–13, 1996. View at: Publisher Site | Google Scholar
  20. L. Caberlotto, Y. L. Hurd, P. Murdock et al., “Neurokinin 1 receptor and relative abundance of the short and long isoforms in the human brain,” European Journal of Neuroscience, vol. 17, no. 9, pp. 1736–1746, 2003. View at: Publisher Site | Google Scholar
  21. J.-P. Lai, S. Lai, F. Tuluc et al., “Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 34, pp. 12605–12610, 2008. View at: Publisher Site | Google Scholar
  22. K. A. DeFea, Z. D. Vaughn, E. M. O'Bryan, D. Nishijima, O. Déry, and N. W. Bunnett, “The proliferative and antiapoptotic effects of substance P are facilitated by formation of a β-arrestin-dependent scaffolding complex,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 20, pp. 11086–11091, 2000. View at: Publisher Site | Google Scholar
  23. Y.-H. Feng, Y. Ding, S. Ren, L. Zhou, C. Xu, and S. S. Karnik, “Unconventional homologous internalization of the angiotensin II type-1 receptor induced by G-protein-independent signals,” Hypertension, vol. 46, no. 2, pp. 419–425, 2005. View at: Publisher Site | Google Scholar
  24. E. Reiter and R. J. Lefkowitz, “GRKs and β-arrestins: roles in receptor silencing, trafficking and signaling,” Trends in Endocrinology and Metabolism, vol. 17, no. 4, pp. 159–165, 2006. View at: Publisher Site | Google Scholar
  25. M. F. Tansky, C. Pothoulakis, and S. E. Leeman, “Functional consequences of alteration of N-linked glycosylation sites on the neurokinin 1 receptor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 25, pp. 10691–10696, 2007. View at: Publisher Site | Google Scholar
  26. J. P. McGillis, M. Mitsuhashi, and D. G. Payan, “Immunomodulation by tachykinin neuropeptides,” Annals of the New York Academy of Sciences, vol. 594, pp. 85–94, 1990. View at: Publisher Site | Google Scholar
  27. M. Muñoz, M. Rosso, A. Pérez et al., “Antitumoral action of the neurokinin-1-receptor antagonist L-733,060 and mitogenic action of substance P on human retinoblastoma cell lines,” Investigative Ophthalmology and Visual Science, vol. 46, no. 7, pp. 2567–2570, 2005. View at: Publisher Site | Google Scholar
  28. H. Friess, Z. Zhu, V. Liard et al., “Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer,” Laboratory Investigation, vol. 83, no. 5, pp. 731–742, 2003. View at: Publisher Site | Google Scholar
  29. R. Kage, S. E. Leeman, and N. D. Boyd, “Biochemical characterization of two different forms of the substance P receptor in rat submaxillary gland,” Journal of Neurochemistry, vol. 60, no. 1, pp. 347–351, 1993. View at: Publisher Site | Google Scholar
  30. H. Li, S. E. Leeman, B. E. Slack et al., “A substance P (neurokinin-1) receptor mutant carboxyl-terminally truncated to resemble a naturally occurring receptor isoform displays enhanced responsiveness and resistance to desensitization,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 17, pp. 9475–9480, 1997. View at: Publisher Site | Google Scholar
  31. J.-C. Beaujouan, M. Saffroy, Y. Torrens, S. Sagan, and J. Glowinski, “Pharmacological characterization of tachykinin septide-sensitive binding sites in the rat submaxillary gland,” Peptides, vol. 20, no. 11, pp. 1347–1352, 1999. View at: Publisher Site | Google Scholar
  32. J.-C. Beaujouan, M. Saffroy, Y. Torrens, and J. Glowinski, “Different subtypes of tachykinin NK1 receptor binding sites are present in the rat brain,” Journal of Neurochemistry, vol. 75, no. 3, pp. 1015–1026, 2000. View at: Publisher Site | Google Scholar
  33. H.-W. Koon, D. Zhao, Y. Zhan, M. P. Moyer, and C. Pothoulakis, “Substance P mediates antiapoptotic responses in human colonocytes by Akt activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 6, pp. 2013–2018, 2007. View at: Publisher Site | Google Scholar
  34. H.-W. Koon, D. Zhao, Y. Zhan, S. Simeonidis, M. P. Moyer, and C. Pothoulakis, “Substance P-stimulated interleukin-8 expression in human colonic epithelial cells involves protein kinase Cδ activation,” Journal of Pharmacology and Experimental Therapeutics, vol. 314, no. 3, pp. 1393–1400, 2005. View at: Publisher Site | Google Scholar
  35. M. Munoz, M. Rosso, and R. Covenas, “The NK-1 receptor: a new target in cancer therapy,” Current Drug Targets, vol. 12, no. 6, pp. 909–921, 2011. View at: Publisher Site | Google Scholar
  36. R. T. Dorsam and J. S. Gutkind, “G-protein-coupled receptors and cancer,” Nature Reviews Cancer, vol. 7, no. 2, pp. 79–94, 2007. View at: Publisher Site | Google Scholar
  37. V. Almendro, S. García-Recio, and P. Gascón, “Tyrosine kinase receptor transactivation associated to G protein-coupled receptors,” Current Drug Targets, vol. 11, no. 9, pp. 1169–1180, 2010. View at: Publisher Site | Google Scholar
  38. E. J. Neer, “Heterotrimeric G proteins: organizers of transmembrane signals,” Cell, vol. 80, no. 2, pp. 249–257, 1995. View at: Publisher Site | Google Scholar
  39. V. L. Lowes, N. Y. Ip, and Y. H. Wong, “Integration of signals from receptor tyrosine kinases and G protein-coupled receptors,” NeuroSignals, vol. 11, no. 1, pp. 5–19, 2002. View at: Publisher Site | Google Scholar
  40. E. J. Neer, “G proteins: critical control points for transmembrane signals,” Protein Science, vol. 3, no. 1, pp. 3–14, 1994. View at: Google Scholar
  41. J. E. Smotrys and M. E. Linder, “Palmitoylation of intracellular signaling proteins: regulation and function,” Annual Review of Biochemistry, vol. 73, pp. 559–587, 2004. View at: Publisher Site | Google Scholar
  42. C. C. Malbon, “G proteins in development,” Nature Reviews Molecular Cell Biology, vol. 6, no. 9, pp. 689–701, 2005. View at: Publisher Site | Google Scholar
  43. S. Guard, A. T. McKnight, K. J. Watling, and S. P. Watson, “Evidence for two types of tachykinin receptors on cholinergic neurons of the guinea pig ileum myenteric plexus,” Annals of the New York Academy of Sciences, vol. 632, pp. 400–403, 1991. View at: Publisher Site | Google Scholar
  44. S. Guard, K. J. Watling, and S. P. Watson, “Neurokinin3-receptors are linked to inositol phospholipid hydrolysis in the guinea-pig ileum longitudinal muscle-myenteric plexus preparation,” British Journal of Pharmacology, vol. 94, no. 1, pp. 148–154, 1988. View at: Publisher Site | Google Scholar
  45. S. Guard and S. P. Watson, “Tachykinin receptor types: classification and membrane signalling mechanisms,” Neurochemistry International, vol. 18, no. 2, pp. 149–165, 1991. View at: Publisher Site | Google Scholar
  46. M. M. Kwatra, D. A. Schwinn, J. Schreurs et al., “The substance P receptor, which couples to Gq/11, is a substrate of β-adrenergic receptor kinase 1 and 2,” The Journal of Biological Chemistry, vol. 268, no. 13, pp. 9161–9164, 1993. View at: Google Scholar
  47. R. Raddatz, C. L. Crankshaw, R. M. Snider, and J. E. Krause, “Similar rates of phosphatidylinositol hydrolysis following activation of wild-type and truncated rat neurokinin-1 receptors,” Journal of Neurochemistry, vol. 64, no. 3, pp. 1183–1191, 1995. View at: Google Scholar
  48. A. Laniyonu, E. Sliwinski-Lis, and N. Fleming, “Different tachykinin receptor subtypes are coupled to the phosphoinositide or cyclic AMP signal transduction pathways in rat submandibular cells,” FEBS Letters, vol. 240, no. 1-2, pp. 186–190, 1988. View at: Publisher Site | Google Scholar
  49. R. D. Ye, “Regulation of nuclear factor κB activation by G-protein-coupled receptors,” Journal of Leukocyte Biology, vol. 70, no. 6, pp. 839–848, 2001. View at: Google Scholar
  50. Y. Nakajima, K. Tsuchida, M. Negishi, S. Ito, and S. Nakanishi, “Direct linkage of three tachykinin receptors to stimulation of both phosphatidylinositol hydrolysis and cyclic AMP cascades in transfected Chinese hamster ovary cells,” The Journal of Biological Chemistry, vol. 267, no. 4, pp. 2437–2442, 1992. View at: Google Scholar
  51. N. Wettschureck and S. Offermanns, “Mammalian G proteins and their cell type specific functions,” Physiological Reviews, vol. 85, no. 4, pp. 1159–1204, 2005. View at: Publisher Site | Google Scholar
  52. J. Meshki, S. D. Douglas, J.-P. Lai, L. Schwartz, L. E. Kilpatrick, and F. Tuluc, “Neurokinin 1 receptor mediates membrane blebbing in HEK293 cells through a Rho/Rho-associated coiled-coil kinase-dependent mechanism,” The Journal of Biological Chemistry, vol. 284, no. 14, pp. 9280–9289, 2009. View at: Publisher Site | Google Scholar
  53. A. J. Morris and C. C. Malbon, “Physiological regulation of G protein-linked signaling,” Physiological Reviews, vol. 79, no. 4, pp. 1373–1430, 1999. View at: Google Scholar
  54. K. Nishimura, J. Frederick, and M. M. Kwatra, “Human substance P receptor expressed in Sf9 cells couples with multiple endogenous G proteins,” Journal of Receptor and Signal Transduction Research, vol. 18, no. 1, pp. 51–65, 1998. View at: Publisher Site | Google Scholar
  55. I.-H. Pang and P. C. Sternweis, “Isolation of the α subunits of GTP-binding regulatory proteins by affinity chromatography with immobilized βγ subunits,” Proceedings of the National Academy of Sciences of the United States of America, vol. 86, no. 20, pp. 7814–7818, 1989. View at: Publisher Site | Google Scholar
  56. R. Williams, X. Zou, and G. W. Hoyle, “Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-kappaB via a Gq-dependent pathway,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 292, no. 2, pp. L430–L437, 2007. View at: Publisher Site | Google Scholar
  57. H. Satake and T. Kawada, “Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors,” Current Drug Targets, vol. 7, no. 8, pp. 963–974, 2006. View at: Publisher Site | Google Scholar
  58. K. L. Bost, “Tachykinin-mediated modulation of the immune response,” Frontiers in Bioscience, vol. 9, pp. 3331–3332, 2004. View at: Publisher Site | Google Scholar
  59. S. G. Macdonald, J. J. Dumas, and N. D. Boyd, “Chemical cross-linking of the substance P (NK-1) receptor to the α subunits of the G proteins Gq and G11,” Biochemistry, vol. 35, no. 9, pp. 2909–2916, 1996. View at: Publisher Site | Google Scholar
  60. A. Kavelaars, D. Broeke, F. Jeurissen et al., “Activation of human monocytes via a non-neurokinin substance P receptor that is coupled to Gi protein, calcium, phospholipase D, MAP kinase, and IL-6 production,” The Journal of Immunology, vol. 153, no. 8, pp. 3691–3699, 1994. View at: Google Scholar
  61. A. Müller, B. Homey, H. Soto et al., “Involvement of chemokine receptors in breast cancer metastasis,” Nature, vol. 410, no. 6824, pp. 50–56, 2001. View at: Publisher Site | Google Scholar
  62. M. Muñoz, M. Berger, M. Rosso, A. Gonzalez-Ortega, A. Carranza, and R. Coveñas, “Antitumor activity of neurokinin-1 receptor antagonists in MG-63 human osteosarcoma xenografts,” International Journal of Oncology, vol. 44, no. 1, pp. 137–146, 2014. View at: Publisher Site | Google Scholar
  63. M. Muñoz and R. Coveñas, “Involvement of substance P and the NK-1 receptor in human pathology,” Amino Acids, vol. 46, no. 7, pp. 1727–1750, 2014. View at: Publisher Site | Google Scholar
  64. M. Munoz, A. Gonzalez-Ortega, M. V. Salinas-Martin et al., “The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer,” International Journal of Oncology, vol. 45, pp. 1658–1672, 2014. View at: Google Scholar
  65. M. Muñoz, M. Rosso, A. Pérez et al., “The NK1 receptor is involved in the antitumoural action of L-733,060 and in the mitogenic action of substance P on neuroblastoma and glioma cell lines,” Neuropeptides, vol. 39, no. 4, pp. 427–432, 2005. View at: Publisher Site | Google Scholar
  66. M. Muñoz, A. Pérez, M. Rosso, C. Zamarriego, and R. Rosso, “Antitumoral action of the neurokinin-1 receptor antagonist L-733 060 on human melanoma cell lines,” Melanoma Research, vol. 14, no. 3, pp. 183–188, 2004. View at: Publisher Site | Google Scholar
  67. M. Muñoz, A. Pérez, R. Coveñas, M. Rosso, and E. Castro, “Antitumoural action of L-733,060 on neuroblastoma and glioma cell lines,” Archives Italiennes de Biologie, vol. 142, no. 2, pp. 105–112, 2004. View at: Google Scholar
  68. C. Palma, F. Nardelli, S. Manzini, and C. A. Maggi, “Substance P activates responses correlated with tumour growth in human glioma cell lines bearing tachykinin NK1 receptors,” British Journal of Cancer, vol. 79, no. 2, pp. 236–243, 1999. View at: Publisher Site | Google Scholar
  69. C. Palma, M. Bigioni, C. Irrissuto, F. Nardelli, C. A. Maggi, and S. Manzini, “Anti-tumour activity of tachykinin NK1 receptor antagonists on human glioma U373 MG xenograft,” British Journal of Cancer, vol. 82, no. 2, pp. 480–487, 2000. View at: Publisher Site | Google Scholar
  70. W. Kolch, G. Heidecker, G. Kochs et al., “Protein kinase Cα activates Raf-1 by direct phosphorylation,” Nature, vol. 364, no. 6434, pp. 249–252, 1993. View at: Publisher Site | Google Scholar
  71. L. R. Howe, S. J. Leevers, N. Gomez, S. Nakielny, P. Cohen, and C. J. Marshall, “Activation of the MAP kinase pathway by the protein kinase raf,” Cell, vol. 71, no. 2, pp. 335–342, 1992. View at: Publisher Site | Google Scholar
  72. R. Marais, Y. Light, C. Mason, H. Paterson, M. F. Olson, and C. J. Marshall, “Requirement of Ras-GTP-Raf complexes for activation of Raf-1 by protein kinase C,” Science, vol. 280, no. 5360, pp. 109–112, 1998. View at: Publisher Site | Google Scholar
  73. T. Palomero, F. Barros, D. del Camino, C. G. Viloria, and P. de La Peña, “A G protein βγ dimer-mediated pathway contributes to mitogen-activated protein kinase activation by thyrotropin-releasing hormone receptors in transfected COS-7 cells,” Molecular Pharmacology, vol. 53, no. 4, pp. 613–622, 1998. View at: Google Scholar
  74. M. Ohmichi, T. Sawada, Y. Kanda et al., “Thyrotropin-releasing hormone stimulates MAP kinase activity in GH3 cells by divergent pathways: evidence of a role for early tyrosine phosphorylation,” The Journal of Biological Chemistry, vol. 269, no. 5, pp. 3783–3788, 1994. View at: Google Scholar
  75. O. Benard, Z. Naor, and R. Seger, “Role of dynamin, Src, and Ras in the protein kinase C-mediated activation of ERK by gonadotropin-releasing hormone,” The Journal of Biological Chemistry, vol. 276, no. 7, pp. 4554–4563, 2001. View at: Publisher Site | Google Scholar
  76. D. C. Budd, G. B. Willars, J. E. McDonald, and A. B. Tobin, “Phosphorylation of the Gq/11-coupled m3-muscarinic receptor is involved in receptor activation of the ERK-1/2 mitogen-activated protein kinase pathway,” The Journal of Biological Chemistry, vol. 276, no. 7, pp. 4581–4587, 2001. View at: Publisher Site | Google Scholar
  77. G. J. Della Rocca, T. Van Biesen, Y. Daaka, D. K. Luttrell, L. M. Luttrell, and R. J. Lefkowitz, “Ras-dependent mitogen-activated protein kinase activation by G protein- coupled receptors,” The Journal of Biological Chemistry, vol. 272, no. 31, pp. 19125–19132, 1997. View at: Publisher Site | Google Scholar
  78. K. A. DeFea, J. Zalevsky, M. S. Thoma, O. Dery, R. D. Mullins, and N. W. Bunnett, “beta-Arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2,” Journal of Cell Biology, vol. 148, no. 6, pp. 1267–1281, 2000. View at: Publisher Site | Google Scholar
  79. L. M. Luttrell, S. S. G. Ferguson, Y. Daaka et al., “β-arrestin-dependent formation of β2 adrenergic receptor-src protein kinase complexes,” Science, vol. 283, no. 5402, pp. 655–661, 1999. View at: Publisher Site | Google Scholar
  80. E. F. Grady, A. M. Garland, P. D. Gamp, M. Lovett, D. G. Payan, and N. W. Bunnett, “Delineation of the endocytic pathway of substance P and its seven-transmembrane domain NK1 receptor,” Molecular Biology of the Cell, vol. 6, no. 5, pp. 509–524, 1995. View at: Publisher Site | Google Scholar
  81. I. Marriott, M. J. Mason, A. Elhofy, and K. L. Bost, “Substance P activates NF-κB independent of elevations in intracellular calcium in murine macrophages and dendritic cells,” Journal of Neuroimmunology, vol. 102, no. 2, pp. 163–171, 2000. View at: Publisher Site | Google Scholar
  82. A. Azzolina, A. Bongiovanni, and N. Lampiasi, “Substance P induces TNF-α and IL-6 production through NFκB in peritoneal mast cells,” Biochimica et Biophysica Acta—Molecular Cell Research, vol. 1643, no. 1–3, pp. 75–83, 2003. View at: Publisher Site | Google Scholar
  83. C.-J. Guo, J.-P. Lai, H.-M. Luo, S. D. Douglas, and W.-Z. Ho, “Substance P up-regulates macrophage inflammatory protein-1β expression in human T lymphocytes,” Journal of Neuroimmunology, vol. 131, no. 1-2, pp. 160–167, 2002. View at: Publisher Site | Google Scholar
  84. K. Lieb, B. L. Fiebich, M. Berger, J. Bauer, and K. Schulze-Osthoff, “The neuropeptide substance P activates transcription factor NF-κB and κB-dependent gene expression in human astrocytoma cells,” The Journal of Immunology, vol. 159, no. 10, pp. 4952–4958, 1997. View at: Google Scholar
  85. W. F. Schwindinger and J. D. Robishaw, “Heterotrimeric G-protein βγ-dimers in growth and differentiation,” Oncogene, vol. 20, no. 13, pp. 1653–1660, 2001. View at: Publisher Site | Google Scholar
  86. M. A. González Moles, A. Mosqueda-Taylor, F. Esteban et al., “Cell proliferation associated with actions of the substance P/NK-1 receptor complex in keratocystic odontogenic tumours,” Oral Oncology, vol. 44, no. 12, pp. 1127–1133, 2008. View at: Publisher Site | Google Scholar
  87. S. S. Wolf, T. W. Moody, R. Quirion, and T. L. O'Donohue, “Biochemical characterization and autoradiographic localization of central substance P receptors using [125I]physalaemin,” Brain Research, vol. 332, no. 2, pp. 299–307, 1985. View at: Publisher Site | Google Scholar
  88. H. Maeno, H. Kiyama, and M. Tohyama, “Distribution of the substance P receptor (NK-1 receptor) in the central nervous system,” Molecular Brain Research, vol. 18, no. 1-2, pp. 43–58, 1993. View at: Publisher Site | Google Scholar
  89. K. Ebner, S. B. Sartori, and N. Singewald, “Tachykinin receptors as therapeutic targets in stress-related disorders,” Current Pharmaceutical Design, vol. 15, no. 14, pp. 1647–1674, 2009. View at: Publisher Site | Google Scholar
  90. G. R. Seabrook, S. L. Shepheard, D. J. Williamson et al., “L-733,060, a novel tachykinin NK1 receptor antagonist; effects in [Ca2+]i mobilisation, cardiovascular and dural extravasation assays,” European Journal of Pharmacology, vol. 317, no. 1, pp. 129–135, 1996. View at: Publisher Site | Google Scholar
  91. S. K. P. Costa, L. M. Yshii, R. N. Poston, M. N. Muscará, and S. D. Brain, “Pivotal role of endogenous tachykinins and the NK1 receptor in mediating leukocyte accumulation, in the absence of oedema formation, in response to TNFalpha in the cutaneous microvasculature,” Journal of Neuroimmunology, vol. 171, no. 1-2, pp. 99–109, 2006. View at: Publisher Site | Google Scholar
  92. A. Eglezos, P. V. Andrews, R. L. Boyd, and R. D. Helme, “Modulation of the immune response by tachykinins,” Immunology and Cell Biology, vol. 69, no. 4, pp. 285–294, 1991. View at: Publisher Site | Google Scholar
  93. P. Robinson, A. Garza, J. Moore et al., “Substance P is required for the pathogenesis of EMCV infection in mice,” International Journal of Clinical and Experimental Medicine, vol. 2, no. 1, pp. 76–86, 2009. View at: Google Scholar
  94. S. A. Green, A. Alon, J. Ianus, K. S. McNaughton, C. A. Tozzi, and T. F. Reiss, “Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence,” Journal of Urology, vol. 176, no. 6, pp. 2535–2540, 2006. View at: Publisher Site | Google Scholar
  95. S. Evangelista, “Involvement of tachykinins in intestinal inflammation,” Current Pharmaceutical Design, vol. 7, no. 1, pp. 19–30, 2001. View at: Publisher Site | Google Scholar
  96. M. Rosso, M. J. Robles-Frías, R. Coveñas, M. V. Salinas-Martín, and M. Muñoz, “The NK-1 receptor is expressed in human primary gastric and colon adenocarcinomas and is involved in the antitumor action of L-733,060 and the mitogenic action of substance P on human gastrointestinal cancer cell lines,” Tumor Biology, vol. 29, no. 4, pp. 245–254, 2008. View at: Publisher Site | Google Scholar
  97. P. Holzer and U. Holzer-Petsche, “Tachykinins in the gut. Part II. Roles in neural excitation, secretion and inflammation,” Pharmacology and Therapeutics, vol. 73, no. 3, pp. 219–263, 1997. View at: Publisher Site | Google Scholar
  98. D. Renzi, B. Pellegrini, F. Tonelli, C. Surrenti, and A. Calabro, “Substance P (neurokinin-1) and neurokinin A (neurokinin-2) receptor gene and protein expression in the healthy and inflamed human intestine,” The American Journal of Pathology, vol. 157, no. 5, pp. 1511–1522, 2000. View at: Publisher Site | Google Scholar
  99. T. Goode, J. O'Connell, P. Anton et al., “Neurokinin-1 receptor expression in inflammatory bowel disease: molecular quantitation and localisation,” Gut, vol. 47, no. 3, pp. 387–396, 2000. View at: Publisher Site | Google Scholar
  100. I. Castagliuolo, A. C. Keates, B. Qiu et al., “Increased substance P responses in dorsal root ganglia and intestinal macrophages during Clostridium difficile toxin A enteritis in rats,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, pp. 4788–4793, 1997. View at: Publisher Site | Google Scholar
  101. S. V. Shrikhande, H. Friess, F. F. Di Mola et al., “NK-1 receptor gene expression is related to pain in chronic pancreatitis,” Pain, vol. 91, no. 3, pp. 209–217, 2001. View at: Publisher Site | Google Scholar
  102. R. Bang, M. Biburger, W. L. Neuhuber, and G. Tiegs, “Neurokinin-1 receptor antagonists protect mice from CD95- and tumor necrosis factor-α-mediated apoptotic liver damage,” Journal of Pharmacology and Experimental Therapeutics, vol. 308, no. 3, pp. 1174–1180, 2004. View at: Publisher Site | Google Scholar
  103. P. S. Satheeshkumar and M. P. Mohan, “NK-1 receptor may have a role in perineural invasion in malignant salivary gland,” Oral Oncology, vol. 50, no. 8, p. e43, 2014. View at: Publisher Site | Google Scholar
  104. S. R. Vigna, “Phosphorylation and desensitization of neurokinin-1 receptor expressed in epithelial cells,” Journal of Neurochemistry, vol. 73, pp. 1925–1932, 1999. View at: Google Scholar
  105. M. Munoz, A. Pavon, M. Rosso et al., “Immunolocalization of NK-1 receptor and Substance P in human normal placenta,” Placenta, vol. 31, pp. 649–651, 2010. View at: Google Scholar
  106. T. A. Almeida, J. Rojo, P. M. Nieto et al., “Tachykinins and tachykinin receptors: structure and activity relationships,” Current Medicinal Chemistry, vol. 11, no. 15, pp. 2045–2081, 2004. View at: Publisher Site | Google Scholar
  107. F. M. Pinto, T. A. Almeida, M. Hernandez, P. Devillier, C. Advenier, and M. L. Candenas, “mRNA expression of tachykinins and tachykinin receptors in different human tissues,” European Journal of Pharmacology, vol. 494, no. 2-3, pp. 233–239, 2004. View at: Publisher Site | Google Scholar
  108. P. Rameshwar, A. Poddar, and P. Gascón, “Hematopoietic regulation mediated by interactions among the neurokinins and cytokines,” Leukemia and Lymphoma, vol. 28, no. 1-2, pp. 1–10, 1997. View at: Google Scholar
  109. P. Rameshwar and P. Gascon, “Substance P (SP) mediates production of stem cell factor and interleukin-1 in bone marrow stroma: potential autoregulatory role for these cytokines in SP receptor expression and induction,” Blood, vol. 86, no. 2, pp. 482–490, 1995. View at: Google Scholar
  110. P. Rameshwar, D. Ganea, and P. Gascón, “In vitro stimulatory effect of substance P on hematopoiesis,” Blood, vol. 81, no. 2, pp. 391–398, 1993. View at: Google Scholar
  111. A. S. Singh, A. Caplan, K. E. Corcoran, J. S. Fernandez, M. Preziosi, and P. Rameshwar, “Oncogenic and metastatic properties of preprotachykinin-I and neurokinin-1 genes,” Vascular Pharmacology, vol. 45, no. 4, pp. 235–242, 2006. View at: Publisher Site | Google Scholar
  112. G. Rao, P. S. Patel, S. P. Idler et al., “Facilitating role of preprotachykinin-I gene in the integration of breast cancer cells within the stromal compartment of the bone marrow: a model of early cancer progression,” Cancer Research, vol. 64, no. 8, pp. 2874–2881, 2004. View at: Publisher Site | Google Scholar
  113. P. S. Bandari, J. Qian, H. S. Oh et al., “Crosstalk between neurokinin receptors is relevant to hematopoietic regulation: cloning and characterization of neurokinin-2 promoter,” Journal of Neuroimmunology, vol. 138, no. 1-2, pp. 65–75, 2003. View at: Publisher Site | Google Scholar
  114. M. Ricardo, K. A. Trzaska, and P. Rameshwar, “Neurokinin-A inhibits cell cycle activators in K562 cells and activates Smad 4 through a non-canonical pathway: a novel method in neural-hematopoietic axis,” Journal of Neuroimmunology, vol. 204, no. 1-2, pp. 85–91, 2008. View at: Publisher Site | Google Scholar
  115. C. De Felipe, J. F. Herrero, J. A. O'Brien et al., “Altered nociception, analgesia and aggression in mice lacking the receptor for substance P,” Nature, vol. 392, no. 6674, pp. 394–397, 1998. View at: Publisher Site | Google Scholar
  116. P. Murtra, A. M. Sheasby, S. P. Hunt, and C. De Felipe, “Rewarding effects of opiates are absent in mice lacking the receptor for substance P,” Nature, vol. 405, no. 6783, pp. 180–183, 2000. View at: Publisher Site | Google Scholar
  117. S. Morcuende, C. A. Gadd, M. Peters et al., “Increased neurogenesis and brain-derived neurotrophic factor in neurokinin-1 receptor gene knockout mice,” European Journal of Neuroscience, vol. 18, no. 7, pp. 1828–1836, 2003. View at: Publisher Site | Google Scholar
  118. M. G. C. van der Hart, B. Czéh, G. de Biurrun et al., “Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume,” Molecular Psychiatry, vol. 7, no. 9, pp. 933–941, 2002. View at: Publisher Site | Google Scholar
  119. B. Bondy, T. C. Baghai, C. Minov et al., “Substance P serum levels are increased in major depression: preliminary results,” Biological Psychiatry, vol. 53, no. 6, pp. 538–542, 2003. View at: Publisher Site | Google Scholar
  120. R. M. Navari, R. R. Reinhardt, R. J. Gralla et al., “Reduction of cisplatin-induced emesis by a selective neurokinin-1- receptor antagonist,” The New England Journal of Medicine, vol. 340, no. 3, pp. 190–195, 1999. View at: Publisher Site | Google Scholar
  121. M. S. Kramer, N. Cutler, J. Feighner et al., “Distinct mechanism for antidepressant activity by blockade of central substance P receptors,” Science, vol. 281, no. 5383, pp. 1640–1645, 1998. View at: Publisher Site | Google Scholar
  122. M. Muñoz and R. Coveñas, “Involvement of substance P and the NK-1 receptor in cancer progression,” Peptides, vol. 48, pp. 1–9, 2013. View at: Publisher Site | Google Scholar
  123. S. Garcia-Recio, G. Fuster, P. Fernandez-Nogueira et al., “Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer,” Cancer Research, vol. 73, no. 21, pp. 6424–6434, 2013. View at: Publisher Site | Google Scholar
  124. G. J. Graham, J. M. Stevens, N. M. Page et al., “Tachykinins regulate the function of platelets,” Blood, vol. 104, no. 4, pp. 1058–1065, 2004. View at: Publisher Site | Google Scholar
  125. D. M. Armstrong, V. M. Pickel, T. H. Joh, D. J. Reis, and R. J. Miller, “Immunocytochemical localization of catecholamine synthesizing enzymes and neuropeptides in area postrema and medial nucleus tractus solitarius of rat brain,” Journal of Comparative Neurology, vol. 196, pp. 505–517, 1981. View at: Publisher Site | Google Scholar
  126. R. M. Navari, “Aprepitant: a neurokinin-1 receptor antagonist for the treatment of chemotherapy-induced nausea and vomiting,” Expert Review of Anticancer Therapy, vol. 4, no. 5, pp. 715–724, 2004. View at: Publisher Site | Google Scholar
  127. B. L. Rapoport, K. Jordan, J. A. Boice et al., “Aprepitant for the prevention of chemotherapy-induced nausea and vomiting associated with a broad range of moderately emetogenic chemotherapies and tumor types: a randomized, double-blind study,” Supportive Care in Cancer, vol. 18, no. 4, pp. 423–431, 2010. View at: Publisher Site | Google Scholar
  128. P. Feyer and K. Jordan, “Update and new trends in antiemetic therapy: the continuing need for novel therapies,” Annals of Oncology, vol. 22, no. 1, pp. 30–38, 2011. View at: Publisher Site | Google Scholar
  129. P. W. Mantyh, “Neurobiology of substance P and the NK1 receptor,” Journal of Clinical Psychiatry, vol. 63, supplement 11, pp. 6–10, 2002. View at: Google Scholar
  130. L. Hilakivi-Clarke, J. Rowland, R. Clarke, and M. E. Lippman, “Psychosocial factors in the development and progression of breast cancer,” Breast Cancer Research and Treatment, vol. 29, no. 2, pp. 141–160, 1994. View at: Publisher Site | Google Scholar
  131. M. Okamura, S. Yamawaki, T. Akechi, K. Taniguchi, and Y. Uchitomi, “Psychiatric disorders following first breast cancer recurrence: prevalence, associated factors and relationship to quality of life,” Japanese Journal of Clinical Oncology, vol. 35, no. 6, pp. 302–309, 2005. View at: Publisher Site | Google Scholar
  132. N. M. J. Rupniak, E. J. Carlson, J. K. Webb et al., “Comparison of the phenotype of NK1R-/- mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs,” Behavioural Pharmacology, vol. 12, no. 6-7, pp. 497–508, 2001. View at: Publisher Site | Google Scholar
  133. S. P. Sivam, J. E. Krause, K. Takeuchi, S. Li, J. F. McGinty, and J.-S. Hong, “Lithium increases rat striatal β- and gamma-preprotachykinin messenger RNAs,” Journal of Pharmacology and Experimental Therapeutics, vol. 248, no. 3, pp. 1297–1301, 1989. View at: Google Scholar
  134. K. Shibata, D. M. Haverstick, and M. J. Bannon, “Tachykinin gene expression in rat limbic nuclei: modulation by dopamine antagonists,” Journal of Pharmacology and Experimental Therapeutics, vol. 255, no. 1, pp. 388–392, 1990. View at: Google Scholar
  135. M. Muñoz, M. Rosso, and R. Coveñas, “Neurokinin-1 receptor antagonists and cancer,” in Focus on Neuropeptide Research, Transworld Research Network, 2007. View at: Google Scholar
  136. M. Muñoz, M. Rosso, and R. Coveñas, “A new frontier in the treatment of cancer: NK-1 receptor antagonists,” Current Medicinal Chemistry, vol. 17, no. 6, pp. 504–516, 2010. View at: Publisher Site | Google Scholar
  137. M. Muñoz, M. Rosso, F. J. Aguilar, M. A. González-Moles, M. Redondo, and F. Esteban, “NK-1 receptor antagonists induce apoptosis and counteract substance P-related mitogenesis in human laryngeal cancer cell line HEp-2,” Investigational New Drugs, vol. 26, no. 2, pp. 111–118, 2008. View at: Publisher Site | Google Scholar
  138. S. Brener, M. A. González-Moles, D. Tostes et al., “A role for the substance P/NK-1 receptor complex in cell proliferation in oral squamous cell carcinoma,” Anticancer Research, vol. 29, no. 6, pp. 2323–2329, 2009. View at: Google Scholar
  139. F. Esteban, M. A. Gonzalez-Moles, D. Castro et al., “Expression of substance P and neurokinin-1-receptor in laryngeal cancer: linking chronic inflammation to cancer promotion and progression,” Histopathology, vol. 54, no. 2, pp. 258–260, 2009. View at: Publisher Site | Google Scholar
  140. U S Food and Drug Administration, http://www.fda.gov/ohrms/dockets/ac/03/briefing/3928B1_01_Merck%20Backgrounder.pdf.
  141. M. Berger, O. Neth, M. Ilmer et al., “Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo,” Journal of Hepatology, vol. 60, no. 5, pp. 985–994, 2014. View at: Publisher Site | Google Scholar
  142. M. Muñoz and M. Rosso, “The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug,” Investigational New Drugs, vol. 28, no. 2, pp. 187–193, 2010. View at: Publisher Site | Google Scholar
  143. S.-C. Huang and V. L. Korlipara, “Neurokinin-1 receptor antagonists: a comprehensive patent survey,” Expert Opinion on Therapeutic Patents, vol. 20, no. 8, pp. 1019–1045, 2010. View at: Publisher Site | Google Scholar
  144. M. Lucattelli, S. Fineschi, P. Geppetti, N. P. Gerard, and G. Lungarella, “Neurokinin-1 receptor blockade and murine lung tumorigenesis,” The American Journal of Respiratory and Critical Care Medicine, vol. 174, no. 6, pp. 674–683, 2006. View at: Publisher Site | Google Scholar
  145. E. Gillespie, S. E. Leeman, L. A. Watts et al., “Truncated neurokinin-1 receptor is increased in colonic epithelial cells from patients with colitis-associated cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 42, pp. 17420–17425, 2011. View at: Publisher Site | Google Scholar
  146. M. Bigioni, A. Benzo, C. Irrissuto, C. A. Maggi, and C. Goso, “Role of NK-1 and NK-2 tachykinin receptor antagonism on the growth of human breast carcinoma cell line MDA-MB-231,” Anti-Cancer Drugs, vol. 16, no. 10, pp. 1083–1089, 2005. View at: Publisher Site | Google Scholar
  147. I. Castagliuolo, L. Valenick, J. Liu, and C. Pothoulakis, “Epidermal growth factor receptor transactivation mediates substance P-induced mitogenic responses in U-373 MG cells,” The Journal of Biological Chemistry, vol. 275, no. 34, pp. 26545–26550, 2000. View at: Publisher Site | Google Scholar
  148. T. A. Castro, M. C. Cohen, and P. Rameshwar, “The expression of neurokinin-1 and preprotachykinin-1 in breast cancer cells depends on the relative degree of invasive and metastatic potential,” Clinical and Experimental Metastasis, vol. 22, no. 8, pp. 621–628, 2005. View at: Publisher Site | Google Scholar
  149. S. D. Douglas and S. E. Leeman, “Neurokinin-1 receptor: functional significance in the immune system in reference to selected infections and inflammation,” Annals of the New York Academy of Sciences, vol. 1217, no. 1, pp. 83–95, 2011. View at: Publisher Site | Google Scholar
  150. K. Yamaguchi, T. Kugimiya, and T. Miyazaki, “Substance P receptor in U373 MG human astrocytoma cells activates mitogen-activated protein kinases ERK1/2 through Src,” Brain Tumor Pathology, vol. 22, no. 1, pp. 1–8, 2005. View at: Publisher Site | Google Scholar
  151. A. M. Khawaja and D. F. Rogers, “Tachykinins: receptor to effector,” The International Journal of Biochemistry & Cell Biology, vol. 28, no. 7, pp. 721–738, 1996. View at: Publisher Site | Google Scholar
  152. B. L. Fiebich, S. Schleicher, R. D. Butcher, A. Craig, and K. Lieb, “The neuropeptide substance P activates p38 mitogen-activated protein kinase resulting in IL-6 expression independently from NF-κB,” Journal of Immunology, vol. 165, no. 10, pp. 5606–5611, 2000. View at: Publisher Site | Google Scholar

Copyright © 2015 Susana Garcia-Recio and Pedro Gascón. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

7567 Views | 1141 Downloads | 71 Citations
 PDF  Download Citation  Citation
 Download other formatsMore
 Order printed copiesOrder

We are committed to sharing findings related to COVID-19 as quickly and safely as possible. Any author submitting a COVID-19 paper should notify us at help@hindawi.com to ensure their research is fast-tracked and made available on a preprint server as soon as possible. We will be providing unlimited waivers of publication charges for accepted articles related to COVID-19.