This review discusses ATP-sensitive potassium (KATP) channels, which connect intracellular energy metabolism to cellular electrical activity and play crucial roles in various physiological processes, particularly in the pancreas and cardiovascular system. KATP channels open when ATP levels decrease during metabolic stress, such as ischemia, helping to protect the heart from injury by maintaining membrane potential and preventing calcium overload. These channels are found in multiple cell types across the cardiovascular system, influencing vascular tone and cardiac excitability. The review highlights the need for further research into the specific expression of KATP channel subunits in humans and the consequences of ischemic events on their functionality. Additionally, it explores the interplay between glycolysis and KATP channels, suggesting that glycolytic ATP can modulate KATP channel activity while emphasizing the cardioprotective effects during ischemic events. The potential for KATP channel openers (KCOs) as therapeutic agents for ischemic heart disease is noted, particularly in improving outcomes in patients undergoing cardiac procedures. Challenges remain in developing specific KCOs with minimal side effects, but advances in precision medicine may enhance targeted therapies in the future. Overall, KATP channels represent promising targets for enhancing cardiovascular health.

IntroductionInvolved in immunity and reproduction, natural killer (NK) cells offer opportunities to develop new immunotherapies to treat infections and cancer or to alleviate pregnancy complications. Most current strategies use cytokines or antibodies to enhance NK-cell function, but none use ion channel modulators, which are widely used in clinical practice to treat hypertension, diabetes, epilepsy, and other conditions. Little is known about ion channels in NK cells. ResultsWe show that Kcnj8, which codes for the Kir6.1 subunit of a certain type of ATP-sensitive potassium (KATP) channel, is highly expressed in murine splenic and uterine NK cells compared to other K+ channels previously identified in NK cells. Kcnj8 expression is highest in the most mature subset of splenic NK cells (CD27-/CD11b+) and in NKG2A+ or Ly49C/I+ educated uterine NK cells. Using patch clamping, we show that a subset of NK cells expresses a current sensitive to the Kir6.1 blocker PNU-37883A. Kcnj8 does not participate in NK cell degranulation in response to tumor cells in vitro or rejection of tumor cells in vivo, or IFN-γ release. Transcriptomics show that genes previously implicated in NK cell development are amongst those differentially expressed in CD27-/CD11b+ NK cells deficient for Kcnj8. Indeed, we found that mice with NK-cell specific Kcnj8 gene ablation have fewer CD27-/CD11b+ and KLRG-1+ NK cells in the bone barrow and spleen. DiscussionThese results show that the KATP subunit Kir6.1 has a key role in NK-cell development.

ATP-sensitive K+ (KATP) channels regulate diverse processes (e.g. insulin secretion from the pancreas and blood flow) but they may also have a role in immunity. Knockout of Kcnj8 (Kir6.1) in mice leads to an exaggerated susceptibility to lipopolysaccharide (LPS). Moreover, a random mutagenesis screen in mice identified the mayday mutation (both Kcnj8 exons deleted) with a profound susceptibility to infection by mouse cytomegalovirus (MCMV) and a ∼20,000-fold sensitization to LPS, poly(I.C) and CpG DNA. Natural killer (NK) cells are effector lymphocytes of the innate immune system that mediate anti-tumor and microbial responses. Despite having key role in immune defenses, their complement of ion channels and how these channels regulate their function are largely uncharacterized compared to other immune cells. We postulated that KATP channels affect NK cell function. Analysis of microarray and RNA-seq mouse ImmGen datasets shows that, compared to other immune cells, Kcnj8 mRNA is expressed selectively and at high levels in natural killer (NK) cells and in CD8+ effector memory T cells after viral infection. We confirmed that Kir6.1 protein is expressed in isolated mouse splenic NK cells. Expansion of mouse splenic NK cells with IL-15 and IL-2 leads to elevated levels of the cytotoxic granzyme and perforin proteins, which is further increased in the presence of the KATP channel opener pinacidil (30 µM). Co-culture of mouse lymphoma YAC-1 cells with mouse splenic NK cells leads to apoptosis progression of the target cells, as well as increased degranulation of NK cells assessed by surface expression of CD107a assessed by flow cytometry. Apoptosis progression and NK cell degranulation were both significantly enhanced by pinacidil (1-30 µM). These data are consistent with a role for KATP channels in NK cell cytotoxicity, possibly by contributing to the release of cytotoxic proteins from NK cells.

Sarcolemmal/plasmalemmal ATP-sensitive K + (K ATP ) channels have key roles in many cell types and tissues. Hundreds of studies have described how the K ATP channel activity and ATP sensitivity can be regulated by changes in the cellular metabolic state, by receptor signaling pathways and by pharmacological interventions. These alterations in channel activity directly translate to alterations in cell or tissue function, that can range from modulating secretory responses, such as insulin release from pancreatic β-cells or neurotransmitters from neurons, to modulating contractile behavior of smooth muscle or cardiac cells to elicit alterations in blood flow or cardiac contractility. It is increasingly becoming apparent, however, that K ATP channels are regulated beyond changes in their activity. Recent studies have highlighted that K ATP channel surface expression is a tightly regulated process with similar implications in health and disease. The surface expression of K ATP channels is finely balanced by several trafficking steps including synthesis, assembly, anterograde trafficking, membrane anchoring, endocytosis, endocytic recycling, and degradation. This review aims to summarize the physiological and pathophysiological implications of K ATP channel trafficking and mechanisms that regulate K ATP channel trafficking. A better understanding of this topic has potential to identify new approaches to develop therapeutically useful drugs to treat K ATP channel-related diseases.

Sarcolemmal/plasmalemmal ATP-sensitive K+ (KATP) channels have key roles in many cell types and tissues. Hundreds of studies have described how the KATP channel activity and ATP sensitivity can be regulated by changes in the cellular metabolic state, by receptor signaling pathways and by pharmacological interventions. These alterations in channel activity directly translate to alterations in cell or tissue function, that can range from modulating secretory responses, such as insulin release from pancreatic β-cells or neurotransmitters from neurons, to modulating contractile behavior of smooth muscle or cardiac cells to elicit alterations in blood flow or cardiac contractility. It is increasingly becoming apparent, however, that KATP channels are regulated beyond changes in their activity. Recent studies have highlighted that KATP channel surface expression is a tightly regulated process with similar implications in health and disease. The surface expression of KATP channels is finely balanced by several trafficking steps including synthesis, assembly, anterograde trafficking, membrane anchoring, endocytosis, endocytic recycling and degradation. This review aims to summarize the physiological and pathophysiological implications of KATP channel trafficking and mechanisms that regulate KATP channel trafficking. A better understanding of this topic has potential to identify new approaches to develop therapeutically useful drugs to treat KATP channel-related diseases.