Calcium signalling and cell-fate choice in B cells

Abstract

B cells receive information that is crucial to their physiology and function through cytosolic Ca²⁺ signals, one of the most important of which is produced by the B-cell receptor (BCR). The BCR Ca²⁺ signal is initiated by inositol-1,4,5-trisphosphate (InsP₃) produced by phospholipase Cγ2 (PLCγ2), which is activated through a positive-feedback loop. If InsP₃ accumulates to a threshold required to maintain endoplasmic reticulum Ca²⁺ store depletion, activation of store-operated Ca²⁺ entry (SOCE) leads to a sustained Ca²⁺ signal. The sensitivity of positive-feedback-loop-mediated activation of PLCγ2 to either augmenting or inhibitory influences renders the amplitude and duration of the Ca²⁺ signal subject to regulation over a wide dynamic range. Microenvironmental cues may indirectly influence B-cell cytosolic Ca²⁺ concentration through contributions to the total pool of activated PLC and InsP₃, or through direct effects on Ca²⁺ fluxes mediated by transporters or channels. One potentially important but often overlooked mechanism for direct regulation of Ca²⁺ 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 Ca²⁺ regulatory mechanisms with present models of how Ca²⁺-dependent signals regulate cell-fate choice in distinct immunological contexts.