Activation mechanisms of store-operated calcium channels in human neutrophils.

Calcium mobilization plays an important role in the regulation of superoxide anion secretion by neutrophils. Intracellular calcium increase is predominantly a result of calcium influx from extracellular media through the opening of calcium-permeable channels, which is subsequent to the emptying of intracellular stores. This capacitative mechanism, referred as store-operated calcium entry (SOCE), implies that depletion of agonist-sensitive intracellular calcium stores generates a secondary signal that promotes plasma membrane calcium influx. Accumulating evidence indicates that three protein families (TRPC, STIM, and Orai) play obligatory roles in the activation of this pathway by forming a ternary heterologous complex on the plasma membrane. This complex might mediate communication between the endoplasmic reticulum and the plasma membrane, perhaps by facilitating coupling between TRPC and inositol 3,4,5-trisposphate receptors. STIM1 behaves as a sensor of Ca2+ level in the endoplasmic reticulum, while Orai 1, by interacting with TRPC and STIM1, might act as a regulatory subunit that operates the transduction of the signals to the calcium-permeable channels on the plasma membrane. The role of the microtubule network in the regulation of SOCE is still obscure. Experiments performed with microtubule inhibitors gave rise to contradictory results, since these compounds induced partial depletion of Ca2+ stores and influx of bivalent cations from extracellular medium in the cytosol, but at the same time they inhibited SOCE triggered by agonists that are known to deplete Ca2+ from the endoplasmic reticulum.