Inhibition of Neutrophil Chemokinesis on Vitronectin by Inhibitors of Calcineurin

• Published in: Science (American Association for the Advancement of Science) 1992-10, Vol.258 (5080), p.296-299
• Main Authors: Hendey, Bill, Klee, Claude B., Maxfield, Frederick R.
• Format: Article
• Language: English
• Subjects: Albumins; Amino Acid Sequence; Aminoquinolines - pharmacology; Biological and medical sciences; Calcineurin; Calcium; Calcium (Nutrient); Calcium in the body; Calcium, Dietary; Calmodulin-Binding Proteins - antagonists & inhibitors; Calmodulin-Binding Proteins - physiology; Carrier Proteins - metabolism; Cell physiology; Chemotaxis, Leukocyte - drug effects; Cytoplasm; Dyes; Enzyme inhibitors; Ethers, Cyclic - pharmacology; Fibrosis; Fluorescence; Fundamental and applied biological sciences. Psychology; Glycoproteins; Humans; Kinetics; Molecular and cellular biology; Molecular Sequence Data; Motility and taxis; N-Formylmethionine Leucyl-Phenylalanine - pharmacology; Neutrophils; Neutrophils - cytology; Neutrophils - drug effects; Neutrophils - physiology; Okadaic Acid; Peptide Fragments - pharmacology; Peptides - pharmacology; Phosphatases; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - physiology; Phosphorylation; Physiological aspects; Physiological regulation; Tacrolimus - pharmacology; Tacrolimus Binding Proteins; Tin; Vitronectin
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1384129

Migration of human polymorphonuclear neutrophils on vitronectin is dependent on repeated transient increases in the concentration of intracellular free calcium ([Ca$^{2+}$]$_i$). A specific peptide inhibitor of the Ca$^{2+}$-calmodulin-dependent phosphatase calcineurin was introduced into the cytoplasm of neutrophils. The peptide inhibited neutrophil migration on vitronectin by interfering with the release of the cells from sites of attachment. A similar reduction in motility on vitronectin occurred when cells were treated with the immunosuppressant FK506, which also inhibits calcineurin when bound to its binding protein, FKBP. These results indicate that a rise in [Ca$^{2+}$]$_i$ reduces integrin-mediated adhesion to vitronectin by a mechanism that requires calcineurin activity.