The serum- and glucocorticoid-inducible kinase-1 (SGK1) is ubiquitously expressed and under genomic control by cell stress (including cell shrinkage) and hormones (including gluco- and mineralocorticoids). Similar to its isoforms SGK2 and SGK3, SGK1 is activated by insulin and growth factors via phosphatidylinositol 3-kinase and the 3-phosphoinositide-dependent kinase PDK1. SGKs activate ion channels (e.g., ENaC, TRPV5, ROMK, Kv1.3, KCNE1/KCNQ1, GluR1, GluR6), carriers (e.g., NHE3, GLUT1, SGLT1, EAAT1–5), and the Na⁺-K⁺-ATPase. They regulate the activity of enzymes (e.g., glycogen synthase kinase-3, ubiquitin ligase Nedd4–2, phosphomannose mutase-2) and transcription factors (e.g., forkhead transcription factor FKHRL1, β-catenin, nuclear factor κB). SGKs participate in the regulation of transport, hormone release, neuroexcitability, cell proliferation, and apoptosis. SGK1 contributes to Na⁺retention and K⁺elimination of the kidney, mineralocorticoid stimulation of salt appetite, glucocorticoid stimulation of intestinal Na⁺/H⁺exchanger and nutrient transport, insulin-dependent salt sensitivity of blood pressure and salt sensitivity of peripheral glucose uptake, memory consolidation, and cardiac repolarization. A common (∼5% prevalence) SGK1 gene variant is associated with increased blood pressure and body weight. SGK1 may thus contribute to metabolic syndrome. SGK1 may further participate in tumor growth, neurodegeneration, fibrosing disease, and the sequelae of ischemia. SGK3 is required for adequate hair growth and maintenance of intestinal nutrient transport and influences locomotive behavior. In conclusion, the SGKs cover a wide variety of physiological functions and may play an active role in a multitude of pathophysiological conditions. There is little doubt that further targets will be identified that are modulated by the SGK isoforms and that further SGK-dependent in vivo physiological functions and pathophysiological conditions will be defined.

Survival of human and animal cells requires avoidance of excessive alterations of cell volume. The osmolarity amassed by cellular accumulation of organic substances must be compensated by lowering cytosolic ion concentrations. The Na+/K+ ATPase extrudes Na+ in exchange for K+, which can permeate the cell membrane through K+ channels. K+ exit generates a cell-negative potential difference across the cell membrane, driving the exit of anions such as Cl-. The low cytosolic Cl- concentrations counterbalance the excess cellular osmolarity by organic substances. Cell volume regulation following cell swelling involves releasing ions through activation of K+ channels and/or anion channels, KCl-cotransport, or parallel activation of K+/H+ exchange and Cl-/HCO3- exchange. Cell volume regulation following cell shrinkage involves accumulation of ions through activation of Na+,K+,2Cl- cotransport, Na+/H+ exchange in parallel to Cl-/HCO3- exchange, or Na+ channels. The Na+ taken up is extruded by the Na+/K+ ATPase in exchange for K+. Shrunken cells further accumulate organic osmolytes such as sorbitol and glycerophosphorylcholine, and monomeric amino acids by altered metabolism and myoinositol (inositol), betaine, taurine, and amino acids by Na+ coupled transport. They release osmolytes during cell swelling. Challenges of cell volume homeostasis include transport, hormones, transmitters, and drugs. Moreover, alterations of cell volume participate in the machinery regulating cell proliferation and apoptotic cell death. Deranged cell volume regulation significantly contributes to the pathophysiology of several disorders such as liver insufficiency, diabetic ketoacidosis, hypercatabolism, fibrosing disease, sickle cell anemia, and infection.

Erythrocyte injury such as osmotic shock, oxidative stress or energy depletion stimulates the formation of prostaglandin E₂ through activation of cyclooxygenase which in turn activates a Ca²⁺ permeable cation channel. Increasing cytosolic Ca²⁺ concentrations activate Ca²⁺ sensitive K⁺ channels leading to hyperpolarization, subsequent loss of KCl and (further) cell shrinkage. Ca²⁺ further stimulates a scramblase shifting phosphatidylserine from the inner to the outer cell membrane. The scramblase is sensitized for the effects of Ca²⁺ by ceramide which is formed by a sphingomyelinase following several stressors including osmotic shock. The sphingomyelinase is activated by platelet activating factor PAF which is released by activation of phospholipase A₂. Phosphatidylserine at the erythrocyte surface is recognised by macrophages which engulf and degrade the affected cells. Moreover, phosphatidylserine exposing erythrocytes may adhere to the vascular wall and thus interfere with microcirculation. Erythrocyte shrinkage and phosphatidylserine exposure (‘eryptosis’) mimic features of apoptosis in nucleated cells which however, involves several mechanisms lacking in erythrocytes. In kidney medulla, exposure time is usually too short to induce eryptosis despite high osmolarity. Beyond that high Cl^- concentrations inhibit the cation channel and high urea concentrations the sphingomyelinase. Eryptosis is inhibited by erythropoietin which thus extends the life span of circulating erythrocytes. Several conditions trigger premature eryptosis thus favouring the development of anemia. On the other hand, eryptosis may be a mechanism of defective erythrocytes to escape hemolysis. Beyond their significance for erythrocyte survival and death the mechanisms involved in ‘eryptosis’ may similarly contribute to apoptosis of nucleated cells.

Exposure of erythrocytes to the Ca²⁺ ionophore ionomycin has recently been shown to induce cell shrinkage, cell membrane blebbing, and breakdown of phosphatidylserine asymmetry, all features typical of apoptosis of nucleated cells. Although breakdown of phosphatidylserine asymmetry is thought to result from activation of a Ca²⁺-sensitive scramblase, the mechanism and role of cell shrinkage have not been explored. The present study was performed to test whether ionomycin-induced activation of Ca²⁺-sensitive Gardos K⁺ channels and subsequent cell shrinkage participate in ionomycin-induced breakdown of phosphatidylserine asymmetry of human erythrocytes. According to on-cell patch-clamp experiments, ionomycin (1 μM) induces activation of inwardly rectifying K⁺-selective channels in the erythrocyte membrane. Fluorescence-activated cell sorter analysis reveals that ionomycin leads to a significant decrease of forward scatter, reflecting cell volume, an effect blunted by an increase of extracellular K⁺ concentration to 25 mM and exposure to the Gardos K⁺ channel blockers charybdotoxin (230 nM) and clotrimazole (5 μM). As reflected by annexin binding, breakdown of phosphatidylserine asymmetry is triggered by ionomycin, an effect again blunted, but not abolished, by an increase of extracellular K⁺ concentration and exposure to charybdotoxin (230 nM) and clotrimazole (5 μM). Similar to ionomycin, glucose depletion leads (within 55 h) to annexin binding of erythrocytes, an effect again partially reversed by an increase of extracellular K⁺ concentration and exposure to charybdotoxin. K-562 human erythroleukemia cells similarly respond to ionomycin with cell shrinkage and annexin binding, effects blunted by antisense, but not sense, oligonucleotides against the small-conductance Ca²⁺-activated K⁺ channel isoform hSK4 (KCNN4). The experiments disclose a novel functional role of Ca²⁺-sensitive K⁺ channels in erythrocytes, i.e., their participation in regulation of erythrocyte apoptosis.