Editorial: Roles of Ion Channels in Immune Cells

摘要

The Editorial on the Research Topic Roles of Ion Channels in Immune Cells Ion channels are critical membrane proteins controlling a wide variety of cellular signaling events in many different cell types. In classical excitable cells, voltage-sensitive ion channels have well-described roles in the regulation of action potentials and contraction events. In non-excitable cells such as circulating or tissue-resident cells of the immune system, ion channels have lesser described roles in controlling cell biology. However, through enhanced pharmacological tools and gene knockouts, we are now beginning to appreciate the plethora of cellular events in immune cells that are controlled by a variety of ion channels ( 1 ). The goal of this research topic was to highlight some of the recent advances in understanding which ion channels are important and are under investigation for novel therapeutics. This collection of six articles covers microglia, myeloid cells, and lymphocytes and provides updates and insights into the roles of various channels in these cells. Mortadza and colleagues review the latest evidence supporting a functional role for transient receptor potential melastatin (TRPM) 2 ion channels in the immune system ( Syed Mortadza et al. ). TRPM2 ion channels are activated by increases in reactive oxygen species (ROS) leading to Ca~(2+)signals in a range of immune cells. The authors discuss the use of TRPM2 knockout mice revealing an important role in the immune system and inflammatory diseases. Based on these studies in mouse models, the authors highlight a negative role for TRPM2 in colitis, ischemia-/reperfusion-mediated tissue damage, and neuropathic and inflammatory pain. They also discuss the importance of TRPM2 in inflammatory signaling including NLRP3 inflammasome activation leading to inflammatory cytokine production including bioactive interleukin (IL)-1β and chemokine-dependent dendritic cell function. Overall, the review demonstrates the importance of TRPM2 as a future therapeutic target for the treatment of inflammatory disease. Stebbing and colleagues provide a mini-review of numerous ion channels expressed in microglia ( Stebbing et al. ). Ligand-gated channels belonging to P2X and N -methyl- d -aspartate (NMDA) receptor families respond to the neurotransmitters adenosine triphosphate (ATP) and glutamate, respectively. These are involved in the sensing of local microenvironments within the central nervous system and can affect microglial activation states through modulation of intracellular Ca~(2+)levels. In addition, K~(+)channels are also implicated in microglial responses including proliferation, nitric oxide generation, and cytokine secretion and, as such, are potential therapeutic targets for increasing neuroprotection in neurodegenerative disorders such as Alzheimer’s disease. Through an original research article, Ferreira and colleagues describe the regulation of the intermediate conductance Ca~(2+)-activated K~(+)channel, KCa3.1, by cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) via a pathway involving ROS and Ca~(2+)/calmodulin-dependent protein kinase II (CaMKII) in microglia ( Ferreira et al. ) KCa3.1 is widely expressed in immune cells, but knowledge of KCa3.1 in microglia is hitherto limited. Through pharmacological approaches, and the use of the rat MLS-9 microglial cell line and alternative-activated primary rat microglia, the authors demonstrate that elevation in cGMP activates PKG to promote mitochondrial ROS formation. This in turn stimulates endoplasmic reticulum Ca~(2+)release, which subsequently binds to calmodulin to both open the KCa3.1 channel and activate CaMKII to increase KCa3.1 activity through a second, unknown mechanism. The authors propose that this process may serve as a positive feedback mechanism to promote KCa3.1-dependent responses in microglia under conditions such as oxidative stress. Moving to the adaptive immune system, Davenport and colleagues have reviewed the current understanding of the Ca_(V)1 subfamily of L-type voltage-gated Ca~(2+)-channels expressed by lymphocytes ( Davenport et al. ). The authors discuss the evidence supporting the expression of Ca_(V)1 ion channels in immune cells including a rare genetic disease (Timothy Syndrome) that suggests a role for Ca_(V)1.2 in human immune responses. Evidence for Ca_(V)1 function in B lymphocytes is largely supported by pharmacological studies, and the authors present further evidence for the expression of Ca_(V)1 ion channels in B lymphocytes using a Ca_(V)1.3 deficient chicken DT40 B cell line. It is concluded that Ca_(V)1 channels play an important role in the immune system; however, there are many unanswered questions particularly surrounding the potential activation mechanism of immune Ca_(V)1 channels. Nohara and colleagues review the current understanding of the complex orchestration of Ca~(2+)responses in T lymphocytes and recent advances in understanding store-operated c