ABSTRACT
Although lacking action potentials, cells of the immune system express distinct sets of ion channels that underlie vital functions in adaptive and innate immune responses. In T lymphocytes that recognize specific antigens and trigger humoral immunity and cell-mediated protection against infectious diseases, the best characterized ion channels include Kv1.3 voltage-gated and KCa3.1 calcium-activated potassium channels; LRRC8 swelling-activated chloride channels; STIM1-activated Orai1 store-operated calcium-selective channels; and TRPM7 channel-kinase and Piezo1 mechanosensitive calcium-permeable nonselective cation channels. A functional network of Orai1, Kv1.3 and KCa3.1 regulates calcium signaling that in turn alters cellular motility, gene expression, secretion of cytokines, cell proliferation and differentiation into T cell subsets. In addition, in T cells and other immune cells, ion channels mediate homeostatic functions, such as maintaining the resting membrane potential, modulating cellular concentrations of monovalent and divalent cations, and regulating cellular volume in response to changes in extracellular tonicity. In neutrophils, Hv1 voltage-gated proton channels and P2RX7 purinergic receptor channels mediate phagocytosis and inflammatory responses to help clear bacterial infections. Charge compensation and proton flux by Hv1 enable and optimize NADPH oxidase activity in many leukocytes. Channel blockers targeting ion channels provide novel therapeutic approaches to dampen autoimmune and inflammatory responses.
