Ion Channels and Transporters in Immunity-Where do We Stand?

Ions are indispensable for cellular integrity. They constitute organellar identity and homeostasis within the physical barrier of biomembranes, support electrical potential across membranes, provide nutritional support, and serve as signaling entities that are able to adapt to varying challenges within milliseconds. Ion channels are the molecular mediators that shuttle ions between the different cellular compartments, often rather unspecific for certain cations or anions, often in a surprisingly selective manner. Their critical role in every cell type is undoubted. Immune cells are specialized cell types with unique molecular properties. They need to be able to rapidly adapt to various kinds of sudden environmental changes, and, to defend the body from dangerous intruders, consequently respond by massive cellular rearrangements in terms of activation, differentiation, or function. These require pronounced molecular rearrangements, among which ions and ion channels take a central part. Within the last two decades, a number of excellent studies have shed light on the role of distinct ion channels and transporters in immunity. Foremost, the identification of the molecular components ORAI and STIM that mediate store-operated calcium signals in activating lymphocytic and innate immune cells has significantly pushed the field toward studying ion movements and their regulation as the basis for understanding immunity.1–3 With the identification of detrimental mutations in ORAIand STIM-encoding genes causing human immunodeficiencies due to lack of appropriate calcium entry machineries,4 the stage was set for a comprehensive investigation of ion channels in health and disease. Since then, we have gained considerable insight into certain ion channel families and mechanisms. Much attention has been attributed to understanding ion homeostasis and ion signaling in T-cell immunity. Very recently, the attention has moved to VGCCs (voltage-gated Ca2+ channel subunits) being relevant in calcium signaling and triggering downstream effector functions in T cells, without functioning as ion channels themselves.5 To date, a growing number of ion-conducting channels and transporters have been identified to modulate T-, B-, NK, and dendritic cell function, monocytes, macrophages, and neutrophils, as well as mast cell homeostasis (Figure 1).3 This is impressive, but we are still far away from understanding the complex relationships of ion conductance and cellular responses, notwithstanding their contribution to (human) diseases. So where do we go from here? In our opinion, there are a few critical questions that will guide our immediate and longterm attention, and require joint efforts to be deciphered. First, it is still partly unclear which ion channels and family members are functionally expressed in diverse immune cell subsets, which proteins they colocalize or interact with, and under which preconditions they are active. We will surely untangle yet unrecognized ion channel members as players in immunity, with hitherto unforeseeable breakthroughs. Also, the contribution of subcellular localization and organellar distribution to distinct functions of ion channels should not be neglected. An interesting example is the report of subsecond-lasting calcium microdomains identified in T cells that shape activation responses via ORAI1, STIM1/2, and RYR1.6