Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 294, Issue 3, Pages L523-L534Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00328.2007
Keywords
intracellular calcium; ryanodine; actin; myosin; lentivirus
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Funding
- NIGMS NIH HHS [R01 GM065281, R01 GM065281-08, R01 GM065281-07, R01 GM065281-09, K08 GM093137, R01 GM065281-06, R01 GM065281-05A1, GM-065281, R01 GM065281-10, R01 GM065281-09S1] Funding Source: Medline
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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 (NK1R, NK2R, and NK3R) classically couple to G(q) protein-mediated inositol 1,4,5-trisphosphate (IP3) synthesis and liberation of intracellular Ca2+, 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 {NK1R, [Sar(9), Met(O-2)(11)]substance P; NK2R, [beta-Ala(8)]- neurokinin A(4-10); NK3R, senktide} stimulated inositol phosphate synthesis and increased intracellular Ca2+ concentration ([Ca2+](i)) in native HASM cells and in HASM cells transfected with each NKR subtype. These effects were blocked by NKR-selective antagonists (NK1R, L-732138; NK2R, GR-159897; NK3R, SB-222200). The initial transient and sustained phases of increased [Ca2+](i) were predominantly inhibited by the IP3 receptor antagonist 2-aminoethoxydiphenyl borate (2-APB) or the store-operated Ca2+ channel antagonist SKF-96365, respectively. These results show that all three subtypes of NKRs are expressed in native HASM cells and that IP3 levels are the primary mediators of NKR-stimulated initial [Ca2+](i) increases, whereas store-operated Ca2+ channels mediate the sustained phase of the [Ca2+](i) increase.
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