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This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/L523    most recent 00328.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mizuta, K. Articles by Emala, C. W. Search for Related Content PubMed PubMed Citation Articles by Mizuta, K. Articles by Emala, C. W., Sr.

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

¹Department of Anesthesiology, College of Physicians and Surgeons of Columbia University, New York, New York; and ²Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Submitted 16 August 2007 ; accepted in final form 15 January 2008

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, [Sar⁹,Met(O₂)¹¹]-substance P; NK₂R, [β-Ala⁸]-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.

intracellular calcium; ryanodine; actin; myosin; lentivirus