Ion channels and transporters in lymphocyte function and immunity

Lymphocyte function is regulated by a network of different ion channels and transporters in the plasma membrane. These ion transport proteins modulate the cytoplasmic concentrations of cations, such as Ca2+, Mg2+ and Zn2+, which function as second messengers and thereby regulate gene expression, lymphocyte differentiation and effector functions.The repertoire of ion channels in lymphocytes includes Ca2+ release-activated Ca2+ (CRAC) channels, P2X receptors, transient receptor potential (TRP) channels, K+ channels, Cl− channels, Mg2+ transporter protein 1 (MAGT1) and Zn2+ transporters of the ZIP and ZNT families.CRAC channels composed of ORAI and stromal interaction molecule (STIM) proteins mediate store-operated Ca2+ entry (SOCE) in lymphocytes following antigen receptor engagement. ORAI1, ORAI2 and ORAI3 constitute the Ca2+-conducting pore of the CRAC channel, whereas STIM1 and STIM2 function as sensors of the Ca2+ concentration in the endoplasmic reticulum and activators of CRAC channels.SOCE is the major pathway for increasing intracellular Ca2+ levels in lymphocytes. Inherited mutations of ORAI1 or STIM1 abolish Ca2+ influx in lymphocytes and result in a severe immunodeficiency syndrome termed CRAC channelopathy.P2X receptors are Ca2+-permeable ion channels activated by extracellular ATP. Genetic deletion or inhibition of P2X receptors impairs T cell function.The voltage-activated K+ channel KV1.3 and the Ca2+-activated K+ channel KCa3.1 regulate the membrane potential of lymphocytes and thereby provide the electrical driving force for the influx of divalent cations such as Ca2+. Inhibition of K+ channels has a profound effect on T cell activation.Mg2+ channels and transporters (such as TRPM7 and MAGT1, respectively) regulate the influx of Mg2+ ions into T cells. Genetic deletion of TRPM7 and inherited mutations in MAGT1 impair T cell function and development.Zn2+ transporters of the ZIP and ZNT families regulate Zn2+ uptake from the gut and Zn2+ levels in various tissues. In lymphocytes, several Zn2+ transporters have recently been reported to mediate Zn2+ signalling and T cell function, but the molecular regulation of these channels and their role in immunity remain to be defined.Several Cl− channels are expressed by lymphocytes, including volume-activated Cl− channels, GABA (γ-aminobutyric acid) receptors and the cystic fibrosis transmembrane conductance regulator (CFTR). These roles of these proteins are currently not well understood in lymphocytes, but they have been implicated in the regulation of apoptosis, cytokine gene expression and T cell-mediated autoimmunity.Inhibition of several ion channels in lymphocytes — such as CRAC channels, K+ channels and P2X receptors — modulates the severity of T cell-mediated autoimmunity and inflammation in animal models of disease, and inhibition of these channels is being explored as an approach to therapeutic immune modulation in patients.