Neurokinin 1 receptor isoforms and the control of innate immunity
ABSTRACT 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.
- SourceAvailable from: Sally I Sharp
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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]. "
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 · 3.27 Impact Factor
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- "CRH also induced mRNA expression of only the truncated NK-1 on LAD2 cells which is known to be at least ten times less sensitive than the full length receptor (Tuluc et al., 2009) and was recently shown to be associated with pathological states (Tuluc et al., 2009). These findings could be relevant for the pathogenesis of skin diseases that worsen by stress (Slominski, 2009), (Slominski et al., 2007), such as psoriasis, where both SP (Remröd et al., 2007) and CRH (Tagen et al., 2007), (Slominski et al., 2000) have been implicated. "
ABSTRACT: Corticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal axis. However, CRH is also secreted outside the brain where it exerts proinflammatory effects through activation of mast cells, which are increasingly implicated in immunity and inflammation. Substance P (SP) is also involved in inflammatory diseases. Human LAD2 leukemic mast cells express only CRHR-1 mRNA weakly. Treatment of LAD2 cells with SP (0.5-2 μM) for 6 hours significantly increases corticotropin-releasing hormone receptor-1 (CRHR-1) mRNA and protein expression. Addition of CRH (1 μM) to LAD2 cells, which are "primed" with SP for 48 hours and then washed, induces synthesis and release of IL-8, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) 24 hours later. These effects are blocked by pretreatment with an NK-1 receptor antagonist. Treatment of LAD2 cells with CRH (1 μM) for 6 hours induces gene expression of NK-1 as compared with controls. However, repeated stimulation of mast cells with CRH (1 μM) leads to downregulation of CRHR-1 and upregulation in NK-1 gene expression. These results indicate that SP can stimulate mast cells and also increase expression of functional CRHR-1, whereas CRH induces NK-1 gene expression. These results may explain CRHR-1 and NK-1 expression in lesional skin of psoriatic patients.Journal of Investigative Dermatology 11/2011; 132(2):324-9. DOI:10.1038/jid.2011.334 · 6.37 Impact Factor
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ABSTRACT: The 4f energy levels and crystal-field parameters for several clusters representing the local coordination surroundings of Eu3+ in the bulk and nanocrystalline cubic Y2O3: Eu3+ crystals are obtained by using a method based on the combination of the DV-Xα calculation and the effective Hamiltonian method initialized by M.F. Reid et al. (J. Phys.: Condens. Matter, 2011, 23: 045501). The results are in reasonable agreement with the measured energy levels and the crystal-field parameters obtained from the least-square fitting. The charge transfer energies are also obtained for all the clusters from the DV-Xα calculation. The results indicate that, compared with the bulk Y2O3: Eu3+ crystal, the charge transfer band in the excitation spectra is red-shifted in the nanocrystal.Current Applied Physics 05/2012; 12(3). DOI:10.1016/j.cap.2011.10.010 · 2.03 Impact Factor