Histamine H4 receptor mediates chemotaxis and calcium mobilization of mast cells

The diverse physiological functions of histamine are mediated through distinct histamine receptors. Mast cells are major producers of histamine, yet effects of histamine on mast cells are currently unclear. The present study shows that histamine induces chemotaxis of mouse mast cells, without affecting mast cell degranulation. Mast cell chemotaxis toward histamine could be blocked by the dual H-3/H-4 receptor antagonist thioperamide, but not by H-1 or H-2 receptor antagonists. This chemotactic response is mediated by the H-4 receptor, because chemotaxis toward histamine was absent in mast cells derived from H-4 receptor-deficient mice but was detected in H-3 receptor-deficient mast cells. In addition, Northern blot analysis showed the expression of H-4 but not H-3 receptors on mast cells. Activation of H-4 receptors by histamine resulted in calcium mobilization from intracellular calcium stores. Both Galphai/o proteins and phospholipase C (PLC) are involved in histamine-induced calcium mobilization and chemotaxis in mast cells, because these responses were completely inhibited by pertussis toxin and PLC inhibitor 1-[6-[[17beta-3-methoxyestra-1,3,5 (10)-trien-17-yl] amino] hexyl]-1H-pyrrole-2,5-dione (U73122). In summary, histamine was shown to mediate signaling and chemotaxis of mast cells via the H-4 receptor. This mechanism might be responsible for mast cell accumulation in allergic tissues.