The function of mast cells is modified by the phosphoinositol-3 (PI3)-kinase pathway. The kinase signals partially through the phosphoinositide-dependent kinase PDK1, which on the one hand activates the serum- and glucocorticoid- inducible kinase SGK1 and on the other hand activates protein kinase PKCδ. SGK1 participates in the stimulation of Ca2+ entry and degranulation, PKCδ inhibits degranulation. The present experiments explored the role of PDK1 in mast cell function. As mice completely lacking PDK1 are not viable, experiments have been performed in mast cells isolated from bone marrow (BMMCs) of PDK1 hypomorphic mice (pdk1hm) and their wild-type littermates (pdk1wt). Antigen stimulation via the FcεRI receptor was followed by Ca2+ entry leading to increase of cytosolic Ca2+ activity in pdk1wt BMMCs, an effect significantly blunted in pdk1hm BMMCs. In contrast, Ca2+ release from intracellular stores was not different between BMMCs of the two genotypes. The currents through Ca2+-activated K+ channels following antigen exposure were again significantly larger in pdk1wt than in pdk1hm cells. The Ca2+ ionophore ionomycin (1 µM) increased the K+ channel conductance to similar values in both genotypes. β-hexosaminidase and histamine release were similar in pdk1wt BMMCs and pdk1hm BMMCs. PKCδ inhibitor rottlerin increased β-hexosaminidase release in pdk1wt BMMCs but not in pdk1hm BMMCs. Phosphorylation of PKCδ and of the SGK1 target NDRG1, was stimulated by the antigen in pdk1wt but not in pdk1hm cells. The observations reveal a role for PDK1 in the regulation of Ca2+ entry into and degranulation of murine mast cells.

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