Gas Signaling Molecules and Mitochondrial Potassium Channels

Abstract

Recently, gaseous signaling molecules, such as carbon monoxide (CO), nitric oxide (NO), and hydrogen sulfide (H2S), which were previously considered to be highly toxic, have been of increasing interest due to their beneficial effects at low concentrations. These so-called gasotransmitters affect many cellular processes, such as apoptosis, proliferation, cytoprotection, oxygen sensing, ATP synthesis, and cellular respiration. It is thought that mitochondria, specifically their respiratory complexes, constitute an important target for these gases. On the other hand, increasing evidence of a cytoprotective role for mitochondrial potassium channels provides motivation for the analysis of the role of gasotransmitters in the regulation of channel function. A number of potassium channels have been shown to exhibit activity within the inner mitochondrial membrane, including ATP-sensitive potassium channels, Ca2+-activated potassium channels, voltage-gated Kv potassium channels, and TWIK-related acid-sensitive K+ channel 3 (TASK-3). The effects of these channels include the regulation of mitochondrial respiration and membrane potential. Additionally, they may modulate the synthesis of reactive oxygen species within mitochondria. The opening of mitochondrial potassium channels is believed to induce cytoprotection, while channel inhibition may facilitate cell death. The molecular mechanisms underlying the action of gasotransmitters are complex. In this review, we focus on the molecular mechanisms underlying the action of H2S, NO, and CO on potassium channels present within mitochondria.

Mitochondrial Potassium Channels as Druggable Targets

“…Mitochondrial potassium channels are regulated by similar factors (as plasma membrane potassium channels) such as ATP, Ca 2+ , ROS, heme, gasotransmitters, or free fatty acids. Additionally, such parameters as membrane potential and/or pH regulate in principle potassium channels in the same way in both the plasma membrane and the mitochondrial inner membrane [15,16,19,[63][64][65].…”

Potential for therapeutic use of hydrogen sulfide in oxidative stress-induced neurodegenerative diseases

“…K ATP channels are considered primary molecular targets for H 2 S. Generally, K ATP channels aid in neurotransmitter release from presynaptic neurons, control seizures, and provide neuroprotection in hypoxic conditions 56. H 2 S hyperpolarizes neurons in the CA1 by K + efflux through ATP-dependent K ATP channels, which are opened as a result of oxidative glutamate toxicity 57.…”

Cardiac function dependence on carbon monoxide

“…While cell stressors may result in cell death, cell proliferation, and neoplasia leading to cellular damage and, possibly, organ failure, endogenous CO can affect the response of the cell to stressors and result in a cytoprotective phenotypic change affecting apoptosis, proliferation, and inflammation. 36 Normal cell processes (including oxygen sensing, adenosine triphosphate (ATP) synthesis, apoptosis, proliferation, cytoprotection, and cellular respiration) are affected and the respiratory complexes of the mitochondria are an important target for CO as well as NO and H 2 S. 37 Established cellular targets of CO include soluble guanylyl cyclase, NO synthase, NADPH oxidase, complex IV of the mitochondrial electron transport chain, and the mitogen-activated protein kinase pathway. Deleterious and beneficial effects have been seen.…”

“… 48 49 51 52 Phosphorylation of BKCa by protein kinase G at specific serines increases the probability of BKCa having an open conformation. 37 Intracellular concentration of cGMP is dependent on guanylate cyclase and cyclic nucleotide degrading enzymes (phosphodiesterases). Membrane bound guanylate cyclase and the soluble forms are activated through different mechanisms – natriuretic peptides for the membrane guanylate cyclase and NO and CO for the cytosolic guanylate cyclase.…”