The Distribution of Neurokinin-1 and Neurokinin-2  Receptors in Human Central Airways

Mapp, C. E.; Miotto, Deborah; Braccioni, Fausto; Saetta, Marina; Turato, Graziella; Maestrelli, Piero; Krause, James E.; Karpitskiy, Vladimir; Boyd, Norman D.; Geppetti, P; Fabbri, Leonardo

doi:10.1164/ajrccm.161.1.9903137

Cited by 84 publications

(48 citation statements)

References 33 publications

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“…Although previous studies of NK-1 receptor localization in the normoxic lung have generated conflicting results, our findings are consistent with previous work suggesting that very few detectable NK-1 receptors are present in the normal distal lung in rats, guinea pigs, or humans (8,17,29).…”

Section: Discussionsupporting

confidence: 91%

Hypoxia upregulates lung microvascular neurokinin-1 receptor expression

Zee

Schomberg²,

Carpenter³

2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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Subacute exposure to moderate hypoxia can promote pulmonary edema formation. The tachykinins, a family of proinflammatory neuropeptides, have been implicated in the pathogenesis of pulmonary edema in some settings, including the pulmonary vascular leak associated with exposure to hypoxia. The effects of hypoxia on tachykinin receptor and peptide expression in the lung, however, remain poorly understood. We hypothesized that subacute exposure to moderate hypoxia increases lung neurokinin-1 (NK-1) receptor expression as well as lung substance P levels. We tested this hypothesis by exposing weanling Sprague-Dawley rats to hypobaric hypoxia (barometric pressure 0.5 atm) for 0, 24, 48, or 72 h. Hypoxia led to time-dependent increases in lung NK-1 receptor mRNA expression and lung NK-1 receptor protein levels at 48 and 72 h of exposure (P Ͻ 0.05). Immunohistochemistry and in situ NK-1 receptor labeling with substance Pconjugated fluorescent nanocrystals demonstrated that hypoxia increased NK-1 expression primarily in the pulmonary microvasculature and in alveolar macrophages. Hypoxia also led to increases in lung substance P levels by 48 and 72 h (P Ͻ 0.05) but led to a decrease in preprotachykinin mRNA levels (P Ͻ 0.05). We conclude that subacute exposure to moderate hypoxia upregulates lung NK-1 receptor expression and lung substance P peptide levels primarily in the lung microvasculature. We speculate that this effect may contribute to the formation of pulmonary edema in the setting of regional or environmental hypoxia. tachykinin; pulmonary edema; acute respiratory distress syndrome ACUTE LUNG INJURY and acute respiratory distress syndrome (ARDS) are clinical syndromes associated with significant morbidity and mortality in humans. The hallmarks of these syndromes are increased pulmonary capillary permeability, pulmonary edema formation, and profound hypoxemia (22). The precise mechanisms that lead to this pulmonary vascular leak remain uncertain (3, 21, 27), although many inflammatory and vasoactive substances have been implicated.Among the mediators implicated in the development of pulmonary edema are the tachykinins. These molecules, a part of the nonadrenergic, noncholinergic nervous system, are a family of peptides that are expressed in the lung in and around the pulmonary vasculature as well as in sensory nerves located primarily near the airways. Substance P, the tachykinin peptide most highly expressed in the lung, exerts its effects primarily through the neurokinin-1 (NK-1) receptor. This ligand-receptor pair mediates neurogenic inflammation in the airways via cytokines including IL-1, 20). In addition, substance P levels are markedly elevated in pulmonary edema fluid from ARDS patients (6), and the NK-1 receptor has been implicated in the pathophysiology of lung injury associated with pancreatitis (13), smoke inhalation (30), and viral infections (23) including respiratory syncytial virus (11).Previous work has also suggested that the tachykinin system may be altered in response to hypoxia. In particular,...

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Section: Discussionsupporting

confidence: 91%

Hypoxia upregulates lung microvascular neurokinin-1 receptor expression

Zee

Schomberg²,

Carpenter³

2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…As in another report , we confirmed the expression of NK2R in a wide range of porcine peripheral tissues. NK2 receptor (as well as NK1 receptor) expression was detected in several structures in human central airways, including smooth muscle, glands, vessels, and pulmonary arteries (Mapp et al 2000). In the respiratory system, the NK2 receptor seems to play an important role during inflammatory states (Bai et al 1995).…”

Section: Oryctolagus Cuniculus Nk2r Sus Scrofa Nk2rmentioning

confidence: 99%

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

Jakimiuk¹,

Podlasz²,

Chmielewska-Krzesińska³

et al. 2017

Vet. Med.

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Substance P is involved in many physiological and pathophysiological processes. This functional diversity is mediated by three neurokinin receptor subtypes (NK1R, NK2R and NK3R) encoded by the TACR1, TACR2 and TACR3 genes, respectively. Despite the increasing interest in using pigs (Sus scrofa) to study human disease mechanisms, the sequences of these receptors are still unconfirmed or in the case of the NK1 receptor, not yet even unpredicted. We employed in silico analysis to define the localisation of the porcine tachykinin receptor genes, and to predict the structures and amino acid sequences of the respective proteins. A reverse transcription polymerase chain reaction (RT-PCR) assay was performed to analyse the expression of tachykinin receptor genes in different porcine tissues. The data show that the TACR1 gene is located on chromosome 3, TACR2 on chromosome 14 and TACR3 on chromosome 8. All three genes encode proteins with structures that incorporate features of G-protein-coupled receptors with sizes of 407, 381 and 464 amino acids, respectively. The receptors display a high degree of similarity to other mammalian neurokinin receptors. The NK1R subtype is expressed in both the central nervous system and peripheral tissues, while NK2R expression seems to be localised mostly to peripheral tissues. The expression of NK3R is found mainly in the central nervous system. This report provides for the first time the results of a comprehensive analysis of the structure and distribution of porcine NK1R, as well as other porcine neurokinin receptors and their genes. We hope that our data may offer an invaluable foundation for the future studies on the function of diverse tachykinin peptides in the central nervous system and peripheral tissues.

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“…Classically, the expression of NK 1 R and NK 2 R has been described in both the nervous system and peripheral target organs, including human airways, whereas the expression of NK 3 R was believed to be more limited to the central and peripheral nervous system (31,34). Furthermore, it has traditionally been thought that only the NK 2 R mediated direct contraction of airway smooth muscle, especially in human airways (3).…”

mentioning

confidence: 99%

“…However, more recently, mRNA encoding the NK 3 R was identified by RT-PCR in human bronchi (48), although the specific lung cell type on which the NK 3 R is expressed is unclear. The NK 1 R and NK 2 R proteins were immunohistochemically detected in human bronchial smooth muscle of central airways, but the presence of the NK 3 R protein was not evaluated (34). Thus the expression and functional coupling of the NK 3 R on human airway smooth muscle is unclear.…”

mentioning

confidence: 99%

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

Mizuta

Gallos

Zhu

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Emala CW Sr. Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 294: L523-L534, 2008. First published January 18, 2008 doi:10.1152/ajplung.00328.2007.-Neuropeptide tachykinins (substance P, neurokinin A, and neurokinin B) are present in peripheral terminals of sensory nerve fibers within the respiratory tract and cause airway contractile responses and hyperresponsiveness in humans and most mammalian species. Three subtypes of neurokinin receptors (NK 1R, NK2R, and NK3R) classically couple to G q protein-mediated inositol 1,4,5-trisphosphate (IP3) synthesis and liberation of intracellular Ca 2ϩ , which initiates contraction, but their expression and calcium signaling mechanisms are incompletely understood in airway smooth muscle. All three subtypes were identified in native and cultured human airway smooth muscle (HASM) and were subsequently overexpressed in HASM cells using a human immunodeficiency virus-1-based lentivirus transduction system. Specific NKR agonists {NK 1R, [Sar 9 ,Met(O2) 11 ]-substance P; NK 2 R, [␤-Ala 8 ]-neurokinin A(4 -10); NK 3 R, senktide} stimulated inositol phosphate synthesis and increased intracellular Ca 2ϩ concentration ([Ca 2ϩ ]i) in native HASM cells and in HASM cells transfected with each NKR subtype. These effects were blocked by NKR-selective antagonists (NK 1R, L-732138; NK2R, GR-159897; NK 3R, SB-222200). The initial transient and sustained phases of increased [Ca 2ϩ ]i were predominantly inhibited by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) or the store-operated Ca 2ϩ channel antagonist SKF-96365, respectively. These results show that all three subtypes of NKRs are expressed in native HASM cells and that IP 3 levels are the primary mediators of NKR-stimulated initial [Ca 2ϩ ] i increases, whereas store-operated Ca 2ϩ channels mediate the sustained phase of the [Ca 2ϩ ]i increase. intracellular calcium; ryanodine; actin; myosin; lentivirus TACHYKININS ARE STORED AND RELEASED from unmyelinated pulmonary C fibers in airways (8,30,31,44) and evoke inflammatory peripheral effects including vasodilation, plasma extravasation, leukocyte adhesion, facilitation of cholinergic neurotransmission, and epithelial cell secretion in the airways (1, 12, 16), which are referred to as neurogenic inflammation. Local release of tachykinins from peripheral sensory nerves may also lead to airway contractile responses and hyperresponsiveness in human and most mammalian species (32, 42). At least three subtypes of neurokinin receptors (NK 1 R, NK 2 R, and NK 3 R) have been characterized, which exhibit preferential affinity for the endogenous neuropeptides substance P, neurokinin A, and neurokinin B, respectively (33). All three receptor subtypes are members of the seven-transmembrane domain receptor superfamily that couple to G q proteins (50).Classically, the expression of NK 1 R and NK 2 R has been described in both the nervous system and p...

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The Distribution of Neurokinin-1 and Neurokinin-2 Receptors in Human Central Airways

Cited by 84 publications

References 33 publications

Hypoxia upregulates lung microvascular neurokinin-1 receptor expression

Hypoxia upregulates lung microvascular neurokinin-1 receptor expression

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

Expression and coupling of neurokinin receptor subtypes to inositol phosphate and calcium signaling pathways in human airway smooth muscle cells

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