Attenuation of murine and human airway contraction by a peptide fragment of the cytoskeleton regulatory protein gelsolin

• Published in: American journal of physiology. Lung cellular and molecular physiology 2019-01, Vol.316 (1), p.L105-L113
• Main Authors: Mikami, Maya, Perez-Zoghbi, Jose F, Zhang, Yi, Emala, Sr, Charles W
• Format: Article
• Language: English
• Subjects: Acetylcholine; Actin; Airway management; Amino acid sequence; Animals; Attenuation; Bradykinin; Bronchoconstriction - drug effects; Calcium; Calcium (intracellular); Contraction; Cytoskeleton; Gelsolin; Gelsolin - chemistry; Gelsolin - pharmacology; Humans; In vivo methods and tests; Inositol trisphosphate; Intracellular; Lungs; Male; Methacholine; Mice; Muscle contraction; Muscle Contraction - drug effects; Muscle, Smooth - metabolism; Muscle, Smooth - pathology; Muscles; Peptides; Peptides - chemistry; Peptides - pharmacology; Phosphatidylinositol 4,5-diphosphate; Phosphatidylinositol 4,5-Diphosphate - metabolism; Proteins; Respiratory system; Respiratory tract; Smooth muscle; Substrates; Synthesis; Trachea - metabolism; Trachea - pathology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00368.2018

We have previously reported that mice genetically deficient in the actin binding protein gelsolin exhibit impaired airway smooth muscle (ASM) relaxation. Primary cultured ASM cells from these mice demonstrate enhanced inositol triphosphate (IP ) synthesis and increased intracellular calcium in response to G -coupled agonists. We hypothesized that this was due to increased intracellular availability of unbound phosphatidylinositol 4,5-bisphosphate (PIP ), based on the fact that gelsolin contains a short peptide region that binds PIP , presumably making it a less available substrate. We now questioned whether a peptide that corresponds to the PIP binding region of gelsolin could modulate ASM signaling and contraction. The 10 amino acid sequence of the gelsolin peptide within the PIP -binding region was incubated with primary cultures of human ASM cells, and IP synthesis was measured in response to a G -coupled agonist. Gelsolin peptide-treated cells generated less IP under basal and bradykinin or acetylcholine (G -coupled) conditions. Acetylcholine-induced contractile force measured in isolated tracheal rings from mice and human tracheal muscle strips in organ baths was attenuated in the presence of the gelsolin peptide. The gelsolin peptide also attenuated methacholine-induced airway constriction in murine precision-cut lung slices. Furthermore, this peptide fragment delivered to the respiratory system of mice via nebulization attenuated subsequent methacholine-induced increases in airway resistance in vivo. The current study demonstrates that introduction of this small gelsolin peptide into the airway may be a novel therapeutic option in bronchoconstrictive diseases.