Expression and function of human hemokinin-1 in human and guinea pig airways

<p>Abstract</p> <p>Background</p> <p>Human hemokinin-1 (hHK-1) and endokinins are peptides of the tachykinin family encoded by the <it>TAC4 </it>gene. <it>TAC4 </it>and hHK-1 expression as well as effects of hHK-1 in the lung and airways remain however unknown and were explored in this study.</p> <p>Methods</p> <p>RT-PCR analysis was performed on human bronchi to assess expression of tachykinin and tachykinin receptors genes. Enzyme immunoassay was used to quantify hHK-1, and effects of hHK-1 and endokinins on contraction of human and guinea pig airways were then evaluated, as well as the role of hHK-1 on cytokines production by human lung parenchyma or bronchi explants and by lung macrophages.</p> <p>Results</p> <p>In human bronchi, expression of the genes that encode for hHK-1, tachykinin NK₁-and NK₂-receptors was demonstrated. hHK-1 protein was found in supernatants from explants of human bronchi, lung parenchyma and lung macrophages. Exogenous hHK-1 caused a contractile response in human bronchi mainly through the activation of NK₂-receptors, which blockade unmasked a NK₁-receptor involvement, subject to a rapid desensitization. In the guinea pig trachea, hHK-1 caused a concentration-dependant contraction mainly mediated through the activation of NK₁-receptors. Endokinin A/B exerted similar effects to hHK-1 on both human bronchi and guinea pig trachea, whereas endokinins C and D were inactive. hHK-1 had no impact on the production of cytokines by explants of human bronchi or lung parenchyma, or by human lung macrophages.</p> <p>Conclusions</p> <p>We demonstrate endogenous expression of <it>TAC4 </it>in human bronchi, the encoded peptide hHK-1 being expressed and involved in contraction of human and guinea pig airways.</p

Involvement of tachykinin receptors in sensitisation to cow's milk proteins in guinea pigs

BACKGROUND—There is growing evidence for a pivotal role for tachykinins in gut neuroimmune interactions. 
AIMS—To determine whether NK1, NK2, and NK3 tachykinin receptors are involved in milk protein induced allergic sensitisation. 
METHODS—Eight groups of 12 Dunkin-Hartley guinea pigs (250-300 g) were used. Four groups were sensitised to milk proteins for three weeks. During this period, these animals were injected intraperitoneally each day with NK1 (SR 140333; 0.3 mg/kg), NK2 (SR 48968; 5 mg/kg), or NK3 (SR 142801; 5 mg/kg) receptor antagonist or vehicle. The fifth group had water available instead of milk and was used as a non-sensitised control. The three other groups received the NK receptor antagonists for three weeks but were not sensitised to milk proteins. 
RESULTS—Sensitised animals treated with NK1 and NK3 receptor antagonists had both lower IgE and IgG serum titres, evaluated by passive cutaneous anaphylaxis, and lower specific IgG serum titres, determined by enzyme linked immunosorbent assay (ELISA), than vehicle treated animals. Sensitisation induced an increase in intestinal mast cell number which was abolished by treatment with the NK1 receptor antagonist. Antigenic challenge-induced jejunal hypersecretion was also blocked by treatment with the NK1 receptor antagonist. 
CONCLUSION—In guinea pigs, NK1 and NK3 but not NK2 receptors are involved in sensitisation to cow's milk. However, NK1 but not NK3 receptor antagonists abolish both the hypermastocytosis induced by food allergy and the hypersecretion induced by antigenic challenge, suggesting different roles for NK1 and NK3 receptors in the mechanisms of sensitisation to β-lactoglobulin. 

 Keywords: NK receptors; tachykinins; food allergy; β-lactoglobulin sensitisation; sensitisation; guinea pi

The NK1 receptor is involved in the neurokinin-induced shape change of rabbit platelets

AbstractSubstance P and selective neurokinin receptor agonists have been tested for their ability to induce shape change in rabbit platelets. Substance P and the NK1 receptor agonist Ac [Arg6,Sar9,Met(O2)11]-substance P (6–11) induced shape change (EC50 = 3 and 6 nM, respectively), whereas the selective NK2 agonist [Nle10]-Neurokinin A (4–10) and the selective NK3 agonist [MePhe7]-Neurokinin B did not show any effect. Moreover, the specific NK1 receptor antagonist CP-96,345 selectively and dose-dependently counteracted the effect of substance P or of the NK1 receptor agonist (IC50 = 2 and 0.8 nM, respectively), whereas the selective NK2 receptor antagonist, SR 48968, had no effect. Unlike for serotonin or low doses of ADP, epinephrine did not allow substance P or the NK1 receptor agonist to become a proaggregating substance. These data therefore show that the NK1 receptor is solely involved in the neurokinin-induced shape change of rabbit platelets

Neuronal bursting induced by NK3 receptor activation in the neonatal rat spinal cord in vitro

Intracellular recording from lumbar motoneurons and extracellular recording from ventral roots of the neonatal rat isolated spinal cord were used to study the mechanisms responsible for the excitation mediated by NK3 tachykinin receptors. The selective NK3 agonists senktide or [MePhe7]neurokinin B induced a slow depolarization with superimposed oscillations (mean period +/- SD was 2.8 +/- 0.8 s) that, in the majority of cases, showed left-right alternation at segmental level and were synchronous between L2 and L5 of the same side. During agonist wash out (5-20 min) a delayed form of hyperexcitability emerged consisting of bursts lasting 8 +/- 2 s (average interburst interval 55 +/- 21 s) with superimposed oscillations usually with homosegmental alternation and heterosegmental synchronicity. Such bursting was accompanied by depression of GABAergic dorsal root potentials evoked by dorsal root stimulation and of the recurrent inhibitory postsynaptic potential recorded from motoneurons. Despite bursting, motoneuron membrane potential returned to baseline while input resistance was increased. Bursts were a network-dependent phenomenon triggered by previous NK3 receptor activation because bursting was suppressed by glutamate receptor antagonists and was insensitive to motoneuron membrane potential or subsequent application of an NK3 receptor antagonist. NK3 receptors operated synergistically with N-methyl-D-aspartate (NMDA) and 5-hydroxytryptamine (5-HT) to trigger fully alternating locomotor-like rhythms while NK3 receptor antagonism disrupted the same rhythm. In summary, in the neonatal rat spinal cord NK3 receptors could trigger rhythmic activity predominantly with alternation at segmental level but with synchronous coupling between ipsilateral motor pools. NK3 receptor activation could also facilitate fictive locomotor patterns induced by NMDA and 5-HT