Calcium signaling in immune cells

Abstract

Calcium acts as a second messenger in many cell types, including lymphocytes. Resting lymphocytes maintain a low concentration of Ca2+. However, engagement of antigen receptors induces calcium influx from the extracellular space by several routes. A chief mechanism of Ca2+ entry in lymphocytes is through store-operated calcium (SOC) channels. The identification of two important molecular components of SOC channels, CRACM1 (the pore-forming subunit) and STIM1 (the sensor of stored calcium), has allowed genetic and molecular manipulation of the SOC entry pathway. In this review, we highlight advances in the understanding of Ca2+ signaling in lymphocytes with special emphasis on SOC entry. We also discuss outstanding questions and probable future directions of the field.

Figure 1

Routes of Ca²⁺ influx and efflux. Routes with similar mechanisms of activation are grouped together here. The probability of activation of a particular mechanism and its eventual contribution toward an increase in cytosolic Ca²⁺ may vary, and all routes may not be active at a given time. Red dots, Ca²⁺; blue dots, Na⁺; green dots, K⁺; ?, controversial route. ROCE, receptor-operated Ca²⁺ entry; K_v, voltage-gated K⁺ channel; K_Ca, Ca²⁺-activated K⁺ channel; PMCA, plasma membrane Ca²⁺ ATPase; Ins(1,4,5)P₃R, Ins(1,4,5)P₃ receptor; TRPV6, transient receptor potential, vanilloid, member 6; ARC, arachidonate-regulated, Ca²⁺-selective; P2 receptors, purinergic receptors; RyR, ryanodine receptor; SERCA, sarco-endoplasmic reticulum Ca²⁺ ATPase; ER, endoplasmic reticulum.

Figure 2

Hypothetical model of the various modes of Ca²⁺ influx in developing, mature and activated T lymphocytes. Top (yellow shaded region), unknown chief source of Ca²⁺ influx; bottom (blue shaded region), SOCE is the main mode of Ca²⁺ influx; +, ++ and +++, reported changes (increases) in the expression of CRACM and STIM mRNA; ?, untested and unknown; −, undetectable; orange ovals, store-independent channels; black ovals, store-dependent channels. TCR, T cell antigen receptor; DP, double-positive.