Alternative Targets for Modulators of Mitochondrial Potassium Channels

Mitochondrial potassium channels control potassium influx into the mitochondrial matrix and thus regulate mitochondrial membrane potential, volume, respiration, and synthesis of reactive oxygen species (ROS). It has been found that pharmacological activation of mitochondrial potassium channels during ischemia/reperfusion (I/R) injury activates cytoprotective mechanisms resulting in increased cell survival. In cancer cells, the inhibition of these channels leads to increased cell death. Therefore, mitochondrial potassium channels are intriguing targets for the development of new pharmacological strategies. In most cases, however, the substances that modulate the mitochondrial potassium channels have a few alternative targets in the cell. This may result in unexpected or unwanted effects induced by these compounds. In our review, we briefly present the various classes of mitochondrial potassium (mitoK) channels and describe the chemical compounds that modulate their activity. We also describe examples of the multidirectional activity of the activators and inhibitors of mitochondrial potassium channels.

The Toxic Effects of Ppz1 Overexpression Involve Nha1-Mediated Deregulation of K+ and H+ Homeostasis

The alteration of the fine-tuned balance of phospho/dephosphorylation reactions in the cell often results in functional disturbance. In the yeast Saccharomyces cerevisiae, the overexpression of Ser/Thr phosphatase Ppz1 drastically blocks cell proliferation, with a profound change in the transcriptomic and phosphoproteomic profiles. While the deleterious effect on growth likely derives from the alteration of multiple targets, the precise mechanisms are still obscure. Ppz1 is a negative effector of potassium influx. However, we show that the toxic effect of Ppz1 overexpression is unrelated to the Trk1/2 high-affinity potassium importers. Cells overexpressing Ppz1 exhibit decreased K+ content, increased cytosolic acidification, and fail to properly acidify the medium. These effects, as well as the growth defect, are counteracted by the deletion of NHA1 gene, which encodes a plasma membrane Na+, K+/H+ antiporter. The beneficial effect of a lack of Nha1 on the growth vanishes as the pH of the medium approaches neutrality, is not eliminated by the expression of two non-functional Nha1 variants (D145N or D177N), and is exacerbated by a hyperactive Nha1 version (S481A). All our results show that high levels of Ppz1 overactivate Nha1, leading to an excessive entry of H+ and efflux of K+, which is detrimental for growth.

De novo variants in SLC12A6 cause sporadic early-onset progressive sensorimotor neuropathy

BackgroundCharcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous disorder of the peripheral nervous system. Biallelic variants in SLC12A6 have been associated with autosomal-recessive hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC). We identified heterozygous de novo variants in SLC12A6 in three unrelated patients with intermediate CMT.MethodsWe evaluated the clinical reports and electrophysiological data of three patients carrying de novo variants in SLC12A6 identified by diagnostic trio exome sequencing. For functional characterisation of the identified variants, potassium influx of mutated KCC3 cotransporters was measured in Xenopus oocytes.ResultsWe identified two different de novo missense changes (p.Arg207His and p.Tyr679Cys) in SLC12A6 in three unrelated individuals with early-onset progressive CMT. All presented with axonal/demyelinating sensorimotor neuropathy accompanied by spasticity in one patient. Cognition and brain MRI were normal. Modelling of the mutant KCC3 cotransporter in Xenopus oocytes showed a significant reduction in potassium influx for both changes.ConclusionOur findings expand the genotypic and phenotypic spectrum associated with SLC12A6 variants from autosomal-recessive HMSN/ACC to dominant-acting de novo variants causing a milder clinical presentation with early-onset neuropathy.

Perioperative Opioid Analgesics of Use in Pain Management for Spine Surgery

This chapter compares the basic properties of several opioid analgesics and explores their applications in perioperative pain control in spine surgery. Parenteral opioids have long been the cornerstone of treatment for postoperative pain; they work by inhibiting voltage-gated calcium channels and increasing potassium influx, which results in reduced neuronal excitability, thereby inhibiting the ascending transmission of painful stimuli and activating the descending inhibitory pathways. This chapter reviews concepts including opioid conversion and rotation, opioid tolerance, and opioid cross-tolerance. It discusses common opioid side effects, and it explores the perioperative use of several specific opioids including remifentanil, sufentanil, methadone, oxycodone, morphine, and tapentadol and discusses their use in spine surgery. Additionally, this chapter discusses patient-controlled analgesia (PCA) and its importance in postoperative pain control.

Overexpression of the vacuolar metal/proton exchanger AtMHX in tomato causes decreased cell expansion and modifications in the mineral content

AtMHX is an Arabidopsis vacuolar transporter that exchanges protons with Mg2+, Zn2+ and Fe2+ ions. Tobacco (Nicotiana tabacum (L.)) plants that overexpressed AtMHX showed necrotic lesions, similar to those shown by plants having increased proton influx from the apoplast into the cytosol. This raised the assumption that AtMHX affects the proton homeostasis of cells. Here, we expressed AtMHX in tomato (Lycopersicon esculentum Mill.). The results clarified that the common response of all plant species in which AtMHX was overexpressed thus far was a reduction in plant mass. Transformed tomato plants, in which this reduction was greater compared with tobacco or Arabidopsis thaliana (L.), exhibited reduced cell expansion and a reduction in potassium content. Modifications were also seen in the content of other minerals, including not only metals that can be carried by AtMHX. These changes may thus reflect not only direct metal transport by AtMHX but also the consequences of reduction in cell size. Decreased cell expansion characterises plants with diminished expression of vacuolar proton pumps, presumably due to reduction in the proton-motive force (PMF) necessary to drive solute (mainly potassium) influx into vacuoles and consequently water uptake. This supported a model in which AtMHX-mediated proton efflux from vacuoles affects the PMF, potassium influx, and cell expansion.