Opening KATP Channels Induces Inflammatory Tolerance and Prevents Chronic Pain

Background: Current treatments for chronic pain are not satisfactory, prompting a frantic search for new therapeutics and new therapeutic targets. Our previous study indicates KATP channel opener has analgesic effect, but the mechanism has not been elucidated. We speculated that KATP channel opener may increase suppressor of cytokine signaling (SOCS)-3 expression to induce inflammatory tolerance and attenuate chronic pain. Methods: The plantar incision (PI) surgery-induced postoperative pain was performed to establish chronic pain model. Growth arrest–specific 6 (Gas6)-/- and Axl-/- mice were used for signaling research. The microglia cell line BV-2 was cultured for in vitro experiments.Results: KATP channel opener significantly attenuated incision-induced mechanical allodynia in mice, associated with the up-regulated expression of SOCS3. Opening KATP channels induced the expression of SOCS3 dependent on Gas6/Axl signaling pathway in microglia. Opening KATP channels inhibits incision-induced mechanical allodynia by activating Gas6/Axl-SOCS3 signaling pathway. Opening KATP channels induces inflammatory tolerance to relieve neuroinflammation and postoperative pain.Conclusions: We demonstrated that KATP channel opening activated Gas6/Axl/SOCS3 signaling to induce inflammatory tolerance and relief chronic pain. We explored a new target for anti-inflammatory and analgesia by regulating the innate immune system, and provide a theoretical basis for clinical preemptive analgesia.

Identification of the Large-Conductance Ca2+-Regulated Potassium Channel in Mitochondria of Human Bronchial Epithelial Cells

Mitochondria play a key role in energy metabolism within the cell. Potassium channels such as ATP-sensitive, voltage-gated or large-conductance Ca2+-regulated channels have been described in the inner mitochondrial membrane. Several hypotheses have been proposed to describe the important roles of mitochondrial potassium channels in cell survival and death pathways. In the current study, we identified two populations of mitochondrial large-conductance Ca2+-regulated potassium (mitoBKCa) channels in human bronchial epithelial (HBE) cells. The biophysical properties of the channels were characterized using the patch-clamp technique. We observed the activity of the channel with a mean conductance close to 285 pS in symmetric 150/150 mM KCl solution. Channel activity was increased upon application of the potassium channel opener NS11021 in the micromolar concentration range. The channel activity was completely inhibited by 1 µM paxilline and 300 nM iberiotoxin, selective inhibitors of the BKCa channels. Based on calcium and iberiotoxin modulation, we suggest that the C-terminus of the protein is localized to the mitochondrial matrix. Additionally, using RT-PCR, we confirmed the presence of α pore-forming (Slo1) and auxiliary β3-β4 subunits of BKCa channel in HBE cells. Western blot analysis of cellular fractions confirmed the mitochondrial localization of α pore-forming and predominately β3 subunits. Additionally, the regulation of oxygen consumption and membrane potential of human bronchial epithelial mitochondria in the presence of the potassium channel opener NS11021 and inhibitor paxilline were also studied. In summary, for the first time, the electrophysiological and functional properties of the mitoBKCa channel in a bronchial epithelial cell line were described.

Opening of ATP sensitive potassium channels causes migraine attacks with aura

Migraine afflicts more than one billion individuals worldwide and is a leading cause of years lived with disability. In about a third of individuals with migraine aura occur in relation to migraine headache. The common pathophysiological mechanisms underlying migraine headache and migraine aura are yet to be identified. Based on recent data, we hypothesized that levcromakalim, an ATP-sensitive potassium channel opener, would trigger migraine attacks with aura in migraine with aura patients.

The KATP channel opener, nicorandil, ameliorates brain damage by modulating synaptogenesis after ischemic stroke

With population growth and aging, more and more patients with cerebral infarction have varying degrees of disability. ATP-sensitive potassium (KATP) channels regulate many cellular functions by coupling metabolic status with cell membrane electrical activity. Nicorandil (N-(2-hydroxyethyl)-nicotinamide nitrate) is the first KATP channel opener approved for clinical use. It has been reported that it might exert protective effects on the cerebral infarction by increasing cerebral blood flow and reducing inflammation. However, only a few studies explored its role in synaptogenesis. We made the rat model of middle cerebral artery occlusion (MCAO). Nicorandil was administered to rats via oral administration immediately after the surgery at a dose of 7.5 mg/kg and then daily for the next days. Infarct volume, cerebral edema, neurological deficits, cognitive impairment, and the level of Synaptophysin (SYP)、Growth associated protein-43 (GAP43) and neuronal nuclear antigen (NeuN) levels were measured to evaluate the effect of nicorandil. Our data showed that nicorandil treatment could decrease brain damage, improve learning and memory, and increase SYP、GAP43 and NeuN level. Taken together, we propose that nicorandil, as an opener of the KATP channel, provides a neuroprotective role in MCAO by promoting synaptic connections.