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Attenuation of Very Late Antigen-5-Mediated Adhesion of Bone Marrow-Derived Mast Cells to Fibronectin by Peptides with Inverted Hydropathy to EF-Hands¹

René Houtman^*, Robert Ten Broeke^*, J. Edwin Blalock, Matteo Villain, Andries S. Koster^2,* and Frans P. Nijkamp^*

^* Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Universiteit Utrecht, Utrecht, The Netherlands; and Department of Physiology and Biophysics, School of Medicine and Dentistry, University of Alabama, Birmingham, AL 35294

Release of allergic mediators from mast cells is enhanced by very late Ag (VLA)-5-mediated interaction of these cells with fibronectin. In this report, we show that VLA-5-mediated adhesion of bone marrow-derived mast cells to fibronectin can be induced by two different pathways: first, FcRI clustering, which depends on calmodulin activation and extracellular Ca²⁺, and, second, by Mn²⁺ stimulation, which is independent of calmodulin activation and antagonized by Ca²⁺. Previous studies have shown the presence of several cation-binding domains in VLA-5 that are homologous to the calcium-binding EF-hands of calmodulin. To show a role for EF-hands of different proteins in VLA-5-mediated adhesion, we used calcium-like peptides (CALP), CALP1 and CALP2, designed to bind to EF-hands based on inverted hydropathy. CALP1 and, more potently, CALP2 inhibited FcRI-induced adhesion to fibronectin via different mechanisms. The target for the effects of CALP1 and 2 on FcRI-induced adhesion and degranulation was intracellular and likely involved calmodulin. Interestingly only CALP2 was able to inhibit Mn²⁺-induced calmodulin-independent adhesion by interfering with an extracellular target, which is probably VLA-5. We conclude that CALP1 and 2 can inhibit VLA-5-mediated adhesion of mast cells to fibronectin through binding to EF-hands of multiple proteins, and that these peptides can be used as lead compounds for the development of future therapy against allergy.

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