Calcium signalling and cell-fate choice in B cells

• Published in: Nature Reviews: Immunology Vol. 7; no. 10; pp. 778 - 789
• Main Authors: Scharenberg, Andrew M., Humphries, Lisa A., Rawlings, David J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2007; Nature Publishing Group
• Subjects: Animals; B cells; B-Lymphocytes - metabolism; Biomedical and Life Sciences; Biomedicine; Calcium; Calcium - metabolism; Calcium channels; Calcium Signaling - physiology; Cellular signal transduction; Cytosol - metabolism; Humans; Immune response; Immunology; Inositol 1,4,5-Trisphosphate - metabolism; Ions; Kinases; Phospholipase C gamma - metabolism; Physiological aspects; Physiology; Receptors, Antigen, B-Cell - physiology; review-article
• DOI: 10.1038/nri2172
• ISSN: 1474-1733; 1474-1741

Key Points B cells receive information that is crucial to their physiology and function through cytosolic Ca 2+ signals, one of the most important of which is produced by the B-cell receptor (BCR). The BCR Ca 2+ signal is initiated by inositol-1,4,5-trisphosphate (InsP 3 ) produced by phospholipase Cγ2 (PLCγ2), which is activated through a positive-feedback loop. If InsP 3 accumulates to a threshold required to maintain endoplasmic reticulum Ca 2+ store depletion, activation of store-operated Ca 2+ entry (SOCE) leads to a sustained Ca 2+ signal. The sensitivity of positive-feedback-loop-mediated activation of PLCγ2 to either augmenting or inhibitory influences renders the amplitude and duration of the Ca 2+ signal subject to regulation over a wide dynamic range. Microenvironmental cues may indirectly influence B-cell cytosolic Ca 2+ concentration through contributions to the total pool of activated PLC and InsP 3 , or through direct effects on Ca 2+ fluxes mediated by transporters or channels. One potentially important but often overlooked mechanism for direct regulation of Ca 2+ fluxes is membrane potential. Differential K + -channel expression in B-cell subsets and newly discovered monovalent selective ion channels of the transient receptor potential melastatin related (TRPM) family provide new mechanisms for dynamic regulation of membrane potential in B cells. Future work will be challenged to integrate the panoply of potential Ca 2+ regulatory mechanisms with present models of how Ca 2+ -dependent signals regulate cell-fate choice in distinct immunological contexts. Fluctuations in cytosolic calcium concentrations affect numerous signals involved in the development and function of B cells. Recent advances have expanded our understanding of the mechanisms involved in the regulation of cytosolic calcium concentrations and how this influences B-cell fate. Alterations in the cytosolic concentration of calcium ions (Ca 2+ ) transmit information that is crucial for the development and function of B cells. Cytosolic Ca 2+ concentration is determined by a balance of active transport and gradient-driven Ca 2+ fluxes, both of which are subject to the influence of multiple receptors and environmental sensing pathways. Recent advances in genomics have allowed for the compilation of an increasingly comprehensive list of Ca 2+ transporters and channels expressed by B cells. The increasing understanding of the function and regulation of these proteins has begun to shift the frontier of Ca 2+ physiology in B cells from molecular analysis to determining how diverse inputs to cytosolic Ca 2+ concentration are integrated in specific immunological contexts.