Store-operated calcium signaling in neutrophils

Abstract

Calcium signals in neutrophils are initiated by a variety of cell-surface receptors, including formyl peptide and other GPCRs, FcRs, and integrins. The predominant pathway by which calcium enters immune cells is termed SOCE, whereby plasma membrane CRAC channels allow influx of extracellular calcium into the cytoplasm when intracellular ER stores are depleted. The identification of 2 key families of SOCE regulators, STIM calcium "sensors" and ORAI calcium channels, has allowed for genetic manipulation of SOCE pathways and provided valuable insight into the molecular mechanism of calcium signaling in immune cells, including neutrophils. This review focuses on our current knowledge of the molecules involved in neutrophil SOCE and how study of these molecules has further informed our understanding of the role of calcium signaling in neutrophil activation.

Keywords: NADPH oxidase; channels; neutrophil activation; sensors.

Figure 1.. Schematic pathway of SOCE in neutrophils, leading to activation of the NAPDH oxidase.

Solid lines indicate known pathways; dotted lines indicate pathways requiring further investigation. Following engagement of surface receptors (shown as green ovals), activation of phospholipase C (PLC) leads to production of IP₃ and DAG. IP₃ activates the IP₃R in the ER, leading to calcium release from ER stores into the cytoplasm. The decrease in calcium concentration in the ER activates calcium sensors STIM1 and potentially STIM2. One or the other (or both; hence, the dotted-line connection) of these sensors couples to surface calcium channels to induce entry of calcium from the extracellular space. The relative contribution of ORAI1, ORAI2, ORAI3, or TRPC channels to calcium entry remains to be investigated. Nevertheless, sustained elevation in intracellular calcium works with DAG to activate PKC isoforms (shown is PKCα and PKCβ; however, PKCδ is also known to be involved [45]), which phosphorylates NADPH subunits and allows assembly of the NADPH oxidase in the plasma/phagosomal membrane for superoxide production. Extracellular calcium influx is also likely coupled to transcriptional changes in neutrophils (shown by the dotted line), probably through calcineurin, as in other immune cells.