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

Mizuta, Kentaro; Gallos, George; Zhu, Deguang; Mizuta, Fumiko; Goubaeva, Farida; Xu, Dingbang; Panettieri, Reynold A.; Yang, Jay; Emala, Charles W.

doi:10.1152/ajplung.00328.2007

Cited by 32 publications

(29 citation statements)

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“…Activation of NK1R couples to G q proteins (14,53), as well as G s (15) and G i and G z (16,54). G q is an important mediator of NK1R activation and leads to activation of PLC that causes phosphatidylinositol 4,5-bisphosphate cleavage to diacylglycerol and IP 3 (53).…”

Section: Discussionmentioning

confidence: 99%

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Neurokinin 1 Receptor Mediates Membrane Blebbing in HEK293 Cells through a Rho/Rho-associated Coiled-coil Kinase-dependent Mechanism

Meshki

Douglas

Lai

et al. 2009

Journal of Biological Chemistry

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We have investigated the effect of neurokinin 1 receptor (NK1R) agonists on HEK293 cells transfected with the NK1R receptor. The NK1R receptor mediates dramatic shape changes that include contractions of the membrane cortex resulting in membrane bleb formation. We have found that the cell shape changes correlate with changes in electrical impedance measured in cellular monolayers. The shape and impedance changes were prevented after preincubation with NK1R antagonists aprepitant and L-73060. Although bleb formation usually heralds apoptotic cell death, we have found that NK1R-mediated cellular blebbing does not associate with apoptosis. Preincubation with a cell-permeable derivative of C3 transferase that blocks Rho or with the Rho-associated coiled-coil kinase inhibitor Y27632 completely prevented NK1R-induced shape and impedance changes. Blebbing was also completely inhibited by ML-9, a myosin light chain kinase inhibitor. Furthermore, the phospholipase C inhibitor U73,122 did not interfere with the effect of Substance P (SP) on cellular morphology and cellular impedance but completely blocked SP-induced intracellular calcium increase, indicating that the blebbing is a process independent of intracellular calcium elevations. Blebbing is a protein kinase C-independent process, since the nonselective protein kinase C inhibitor GF109203X did not interfere with SP-induced effects. Based on these results, we provide the first evidence that NK1R receptorligand interaction can cause apoptosis-independent cellular blebbing and that this process is mediated by the Rho/Rho-associated coiled-coil kinase pathway.

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Section: Discussionmentioning

confidence: 99%

“…G q is an important mediator of NK1R activation and leads to activation of PLC that causes phosphatidylinositol 4,5-bisphosphate cleavage to diacylglycerol and IP 3 (53). The release of IP 3 ultimately leads to release of internal stores of calcium.…”

Section: Discussionmentioning

confidence: 99%

Neurokinin 1 Receptor Mediates Membrane Blebbing in HEK293 Cells through a Rho/Rho-associated Coiled-coil Kinase-dependent Mechanism

Meshki

Douglas

Lai

et al. 2009

Journal of Biological Chemistry

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“…Cells were stably transfected as previously described (25), with modifications detailed in the online supplement.…”

Section: M3 Transfectionmentioning

confidence: 99%

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Townsend

Zhang

et al. 2014

Am J Respir Cell Mol Biol

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b-Agonists are the first-line therapy to alleviate asthma symptoms by acutely relaxing the airway. Purified components of ginger relax airway smooth muscle (ASM), but the mechanisms are unclear. By elucidating these mechanisms, we can explore the use of phytotherapeutics in combination with traditional asthma therapies. The objectives of this study were to: (1) determine if 6-gingerol, 8-gingerol, or 6-shogaol potentiate b-agonist-induced ASM relaxation; and (2) define the mechanism(s) of action responsible for this potentiation. Human ASM was contracted in organ baths. Tissues were relaxed dose dependently with b-agonist, isoproterenol, in the presence of vehicle, 6-gingerol, 8-gingerol, or 6-shogaol (100 mM). Primary human ASM cells were used for cellular experiments. Purified phosphodiesterase (PDE) 4D or phospholipase C b enzyme was used to assess inhibitory activity of ginger components using fluorescent assays. A G-LISA assay was used to determine the effects of ginger constituents on Ras homolog gene family member A activation. Significant potentiation of isoproterenol-induced relaxation was observed with each of the ginger constituents. 6-Shogaol showed the largest shift in isoproterenol half-maximal effective concentration. 6-Gingerol, 8-gingerol, or 6-shogaol significantly inhibited PDE4D, whereas 8-gingerol and 6-shogaol also inhibited phospholipase C b activity. 6-Shogaol alone inhibited Ras homolog gene family member A activation. In human ASM cells, these constituents decreased phosphorylation of 17-kD protein kinase C-potentiated inhibitory protein of type 1 protein phosphatase and 8-gingerol decreased myosin light chain phosphorylation. Isolated components of ginger potentiate b-agonist-induced relaxation in human ASM. This potentiation involves PDE4D inhibition and cytoskeletal regulatory proteins. Together with b-agonists, 6-gingerol, 8-gingerol, or 6-shogaol may augment existing asthma therapy, resulting in relief of symptoms through complementary intracellular pathways.Keywords: asthma; adrenergic receptor; myosin light chain; lung; bronchodilation Clinical RelevanceNatural herbal remedies, including ginger, have long been used to treat respiratory conditions. Many individuals with asthma use herbal therapies to self-treat their asthma symptoms; however, little is known regarding how these compounds work in the airway. In the current work, we show that 6-gingerol, 8-gingerol, and 6-shogaol potentiate b-agonist-induced relaxation of airway smooth muscle by inhibiting both phosphodiesterase 4D and phosphatidylinositol-specific phospholipase C, leading to downstream regulation of contractile proteins. These data suggest that natural compounds can work in combination with traditional asthma therapies to relieve asthma symptoms.

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“…Multiple genes for tachykinins, eg, TAC1 coding for SP and NKA, TAC3 coding for NKB, and TAC4 coding for HK-1/endokinins, have been identified (3) and believed to be the result of gene duplication occurred during vertebrate evolution (4). The biological actions of tachykinins are mediated by 3 major types of neurokinin receptors (NKRs), namely NK1R, NK2R, and NK3R (3), which are class I G protein-coupled receptors functionally coupled with phospholipase C (PLC)/inositol 1,4,5-triphosphate (IP 3 )/protein kinase C (PKC), MAPK, cAMP/protein kinase A (PKA), and Ca 2ϩ -dependent cascades (5)(6)(7)(8)(9)(10). Individual NKR subtypes are known to exhibit differential binding for different tachykinins, with NK1R preferring SP, NK2R preferring NKA, and NK3R preferring NKB, respectively (3).…”

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confidence: 99%

Novel Pituitary Actions of TAC3 Gene Products in Fish Model: Receptor Specificity and Signal Transduction for Prolactin and Somatolactin α Regulation by Neurokinin B (NKB) and NKB-Related Peptide in Carp Pituitary Cells

et al. 2014

Endocrinology

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TAC3 is a member of tachykinins, and its gene product neurokinin B (NKB) has recently emerged as a key regulator for LH through modulation of kisspeptin/GnRH system within the hypothalamus. In fish models, TAC3 not only encodes NKB but also a novel tachykinin-like peptide called NKB-related peptide (NKBRP), and the pituitary actions of these TAC3 gene products are still unknown. Using grass carp as a model, the direct effects and postreceptor signaling for the 2 TAC3 products were examined at the pituitary level. Grass carp TAC3 was cloned and confirmed to encode NKB and NKBRP similar to that of other fish species. In carp pituitary cells, NKB and NKBRP treatment did not affect LH release and gene expression but up-regulated prolactin (PRL) and somatolactin (SL)α secretion, protein production, and transcript expression. The stimulation by these 2 TAC3 gene products on PRL and SLα release and mRNA levels were mediated by pituitary NK2 and NK3 receptors, respectively. Apparently, NKB- and NKBRP-induced SLα secretion and transcript expression were caused by adenylate cyclase/cAMP/protein kinase A, phospholipase C/inositol 1,4,5-triphosphate/protein kinase C and Ca(2+)/calmodulin/Ca(2+)/calmodulin-dependent protein kinase II activation. The signal transduction for the corresponding responses on PRL release and mRNA expression were also similar, except that the protein kinase C component was not involved. These findings suggest that the 2 TAC3 gene products do not play a role in LH regulation at the pituitary level in carp species but may serve as novel stimulators for PRL and SLα synthesis and secretion via overlapping postreceptor signaling mechanisms coupled to NK2 and NK3 receptors, respectively.

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

Cited by 32 publications

References 58 publications

Neurokinin 1 Receptor Mediates Membrane Blebbing in HEK293 Cells through a Rho/Rho-associated Coiled-coil Kinase-dependent Mechanism

Neurokinin 1 Receptor Mediates Membrane Blebbing in HEK293 Cells through a Rho/Rho-associated Coiled-coil Kinase-dependent Mechanism

Active Components of Ginger Potentiate β-Agonist–Induced Relaxation of Airway Smooth Muscle by Modulating Cytoskeletal Regulatory Proteins

Novel Pituitary Actions of TAC3 Gene Products in Fish Model: Receptor Specificity and Signal Transduction for Prolactin and Somatolactin α Regulation by Neurokinin B (NKB) and NKB-Related Peptide in Carp Pituitary Cells

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