Neurokinin 1 receptor isoforms and the control of innate immunity

Joseph Stokes Jr. Research Institute, The Children's Hospital of Philadelphia, USA.
Trends in Immunology (Impact Factor: 10.4). 06/2009; 30(6):271-6. DOI: 10.1016/
Source: PubMed


Substance P is the prototype tachykinin peptide and triggers a variety of biological effects in both the nervous and immune system. Two naturally occurring variants of the neurokinin 1 receptor (NK1R) mediate the effects of SP: a 'classic' full-length receptor and a truncated (tail-less) form that lacks 96 amino acid residues at the C-terminus. Most research has focused on the full length receptor and the truncated NK1R has not been extensively explored. Recent data demonstrate that truncated NK1R has important functional roles, including modulation of responses triggered by cytokines, chemotaxis of macrophages and regulation of HIV replication. Targeting the truncated NK1R with pharmacologic agents might result in novel therapeutic approaches in diseases which affect the immune system, including HIV disease.

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    • "Truncated NK1R lacks 96 amino acid residues corresponding to the C-terminus of the full length receptor. Furthermore, activation of full length and truncated NK1R results in differential receptor signalling mediated by different G-proteins [Tuluc et al., 2009] and the truncated form has a 10-fold lower binding affinity to substance P than the long form [Fong et al., 1992]. The long NK1R isoform is prevalent throughout the human brain, while the truncated form is more common in peripheral tissues, but to date there is little evidence for a regionspecific role for the two isoforms in the CNS [Caberlotto et al., 2003]. "
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    ABSTRACT: Single nucleotide polymorphisms (SNPs) in the tachykinin receptor 1 gene (TACR1) are nominally associated with bipolar affective disorder (BPAD) in a genome-wide association study and in several case-control samples of BPAD, alcohol dependence syndrome (ADS) and attention-deficit hyperactivity disorder (ADHD). Eighteen TACR1 SNPs were associated with BPAD in a sample (506 subjects) from University College London (UCL1), the most significant being rs3771829, previously associated with ADHD. To further elucidate the role of TACR1 in affective disorders, rs3771829 was genotyped in a second BPAD sample of 593 subjects (UCL2), in 997 subjects with ADS, and a subsample of 143 individuals diagnosed with BPAD and comorbid alcohol dependence (BPALC). rs3771829 was associated with BPAD (UCL1 and UCL2 combined: P = 2.0 × 10−3), ADS (P = 2.0 × 10−3) and BPALC (P = 6.0 × 10−4) compared with controls screened for the absence of mental illness and alcohol dependence. DNA sequencing in selected cases of BPAD and ADHD who had inherited TACR1-susceptibility haplotypes identified 19 SNPs in the promoter region, 5′ UTR, exons, intron/exon junctions and 3′ UTR of TACR1 that could increase vulnerability to BPAD, ADS, ADHD, and BPALC. Alternative splicing of TACR1 excludes intron 4 and exon 5, giving rise to two variants of the neurokinin 1 receptor (NK1R) that differ in binding affinity of substance P by 10-fold. A mutation in intron four, rs1106854, was associated with BPAD, although a regulatory role for rs1106854 is unclear. The association with TACR1 and BPAD, ADS, and ADHD suggests a shared molecular pathophysiology between these affective disorders. © 2014 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2014; 165(4). DOI:10.1002/ajmg.b.32241 · 3.42 Impact Factor
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    • "For asthma that is inadequately controlled with low to moderate concentrations of inhaled corticosteroids, it is an accepted practice to progressively increase the concentration to achieve disease control. However, because inhaled corticosteroids have a relatively flat concentration-response curve [38], the beneficial effects on inflammation and asthma symptoms might be accompanied by local or systemic side effects. This concern prompted the pioneering studies of Greening et al. [39] and Woolcock et al. [40], who investigated the effect of adding the long-acting β2-agonist SM (SM) in combination with existing inhaled corticosteroid treatment, compared to the use of higher concentrations of inhaled beclomethasone dipropionate, in asthma patients with persistent symptoms. "
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    ABSTRACT: Despite the fact that glucocorticoids and long acting beta agonists are effective treatments for asthma, their effects on human mast cells (MC) appear to be modest. Although MC are one of the major effector cells in the underlying inflammatory reactions associated with asthma, their regulation by these drugs is not yet fully understood and, in some cases, controversial. Using a human immortalized MC line (LAD2), we studied the effects of fluticasone propionate (FP) and salmeterol (SM), on the release of early and late phase mediators. LAD2 cells were pretreated with FP (100 nM), SM (1 µM), alone and in combination, at various incubation times and subsequently stimulated with agonists substance P, C3a and IgE/anti-IgE. Degranulation was measured by the release of β-hexosaminidase. Cytokine and chemokine expression were measured using quantitative PCR, ELISA and cytometric bead array (CBA) assays. The combination of FP and SM synergistically inhibited degranulation of MC stimulated with substance P (33% inhibition compared to control, n = 3, P<.05). Degranulation was inhibited by FP alone, but not SM, when MC were stimulated with C3a (48% inhibition, n = 3, P<.05). As previously reported, FP and SM did not inhibit degranulation when MC were stimulated with IgE/anti-IgE. FP and SM in combination inhibited substance P-induced release of tumor necrosis factor (TNF), CCL2, and CXCL8 (98%, 99% and 92% inhibition, respectively, n = 4, P<.05). Fluticasone and salmeterol synergistically inhibited mediator production by human MC stimulated with the neuropeptide substance P. This synergistic effect on mast cell signaling may be relevant to the therapeutic benefit of combination therapy in asthma.
    PLoS ONE 05/2014; 9(5):e96891. DOI:10.1371/journal.pone.0096891 · 3.23 Impact Factor
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    • "The undecapeptide substance P (SP) is the prototype tachykinin and it has been identified in the central and peripheral nervous system, and in the immune system [112]. SP, as a primary sensory neurotransmitter, is found in the smaller, unmyelinated sensory ‘painful’ fibers [113]. "
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    ABSTRACT: Infection of the nervous system with the human immunodeficiency virus (HIV-1) can lead to cognitive, motor and sensory disorders. HIV-related sensory neuropathy (HIV-SN) mainly contains the HIV infection-related distal sensory polyneuropathy (DSP) and antiretroviral toxic neuropathies (ATN). The main pathological features that characterize DSP and ATN include retrograde ("dying back") axonal degeneration of long axons in distal regions of legs or arms, loss of unmyelinated fibers, and variable degree of macrophage infiltration in peripheral nerves and dorsal root ganglia (DRG). One of the most common complaints of HIV-DSP is pain. Unfortunately, many conventional agents utilized as pharmacologic therapy for neuropathic pain are not effective for providing satisfactory analgesia in painful HIV-related distal sensory polyneuropathy, because the molecular mechanisms of the painful HIV-SDP are not clear in detail. The HIV envelope glycoprotein, gp120, appears to contribute to this painful neuropathy. Recently, preclinical studies have shown that glia activation in the spinal cord and DRG has become an attractive target for attenuating chronic pain. Cytokines/chemokines have been implicated in a variety of painful neurological diseases and in animal models of HIV-related neuropathic pain. Mitochondria injured by ATN and/or gp120 may be also involved in the development of HIV-neuropathic pain. This review discusses the neurochemical and pharmacological mechanisms of HIV-related neuropathic pain based on the recent advance in the preclinical studies, providing insights into novel pharmacological targets for future therapy.
    Current Neuropharmacology 09/2013; 11(5):499-512. DOI:10.2174/1570159X11311050005 · 3.05 Impact Factor
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