Fundamental Ca2+ Signaling Mechanisms in Mouse Dendritic Cells: CRAC Is the Major Ca2+ Entry Pathway

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Abstract
Although Ca2+-signaling processes are thought to underlie many dendritic cell (DC) functions, the Ca2+ entry pathways are unknown. Therefore, we investigated Ca2+-signaling in mouse myeloid DC using Ca2+ imaging and electrophysiological techniques. Neither Ca2+ currents nor changes in intracellular Ca2+ were detected following membrane depolarization, ruling out the presence of functional voltage-dependent Ca2+ channels. ATP, a purinergic receptor ligand, and 1–4 dihydropyridines, previously suggested to activate a plasma membrane Ca2+ channel in human myeloid DC, both elicited Ca2+ rises in murine DC. However, in this study these responses were found to be due to mobilization from intracellular stores rather than by Ca2+ entry. In contrast, Ca2+ influx was activated by depletion of intracellular Ca2+ stores with thapsigargin, or inositol trisphosphate. This Ca2+ influx was enhanced by membrane hyperpolarization, inhibited by SKF 96365, and exhibited a cation permeability similar to the Ca2+ release-activated Ca2+ channel (CRAC) found in T lymphocytes. Furthermore, ATP, a putative DC chemotactic and maturation factor, induced a delayed Ca2+ entry with a voltage dependence similar to CRAC. Moreover, the level of phenotypic DC maturation was correlated with the extracellular Ca2+ concentration and enhanced by thapsigargin treatment. These results suggest that CRAC is a major pathway for Ca2+ entry in mouse myeloid DC and support the proposal that CRAC participates in DC maturation and migration.