Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Kshatri, Aravind; Gonzalez-Hernandez, Alberto J.; Giráldez, Teresa

doi:10.3389/fnmol.2018.00258

Cited by 101 publications

(97 citation statements)

References 252 publications

(305 reference statements)

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“…This interaction inhibits the BK K + currents, and the inhibition is partially removed by acidification; thus, acidification would increase the BK currents. BK channels can have different functions, depending on the context, and it was shown in several studies that increased BK currents result in a faster recovery of Na + channels from inactivation and increase therefore neuronal excitability (Kshatri et al, 2018). BK current densities and neuronal excitability were indeed higher in neurons of ASIC1a/2/3 −/− mice (Petroff et al, 2012).…”

Section: Discussionmentioning

confidence: 96%

Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons

Alijevic

Bignucolo

Hichri

et al. 2020

Front. Cell. Neurosci.

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Acid-sensing ion channels (ASICs) are H +-activated neuronal Na + channels. They are involved in fear behavior, learning, neurodegeneration after ischemic stroke and in pain sensation. ASIC activation has so far been studied only with fast pH changes, although the pH changes associated with many roles of ASICs are slow. It is currently not known whether slow pH changes can open ASICs at all. Here, we investigated to which extent slow pH changes can activate ASIC1a channels and induce action potential signaling. To this end, ASIC1a current amplitudes and charge transport in transfected Chinese hamster ovary cells, and ASIC-mediated action potential signaling in cultured cortical neurons were measured in response to defined pH ramps of 1-40 s duration from pH 7.4 to pH 6.6 or 6.0. A kinetic model of the ASIC1a current was developed and integrated into the Hodgkin-Huxley action potential model. Interestingly, whereas the ASIC1a current amplitude decreased with slower pH ramps, action potential firing was higher upon intermediate than fast acidification in cortical neurons. Indeed, fast pH changes (<4 s) induced short action potential bursts, while pH changes of intermediate speed (4-10 s) induced longer bursts. Slower pH changes (>10 s) did in many experiments not generate action potentials. Computer simulations corroborated these observations. We provide here the first description of ASIC function in response to defined slow pH changes. Our study shows that ASIC1a currents, and neuronal activity induced by ASIC1a currents, strongly depend on the speed of pH changes. Importantly, with pH changes that take >10 s to complete, ASIC1a activation is inefficient. Therefore, it is likely that currently unknown modulatory mechanisms allow ASIC activity in situations such as ischemia and inflammation.

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Section: Discussionmentioning

confidence: 96%

Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons

Alijevic

Bignucolo

Hichri

et al. 2020

Front. Cell. Neurosci.

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“…K Ca channels play a functional role by coupling the increase of intracellular Ca 2+ to the hyperpolarization of the membrane potential. This feature enables K Ca channels to play key roles in regulating cell excitability and K + homeostasis [ 25 ]. The K Ca channels are divided into three subfamilies that include small conductance K Ca (SK Ca ) channels, large or big K Ca (BK Ca ), and intermediate K Ca (IK Ca ).…”

Section: Discussionmentioning

confidence: 99%

Vasodilatory Effect of Phellinus linteus Extract in Rat Mesenteric Arteries

et al. 2020

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: Phellinus linteus is a well-known medicinal mushroom that is widely used in Asian countries. In several experimental models, Phellinus linteus extracts were reported to have various biological effects, including anti-inflammatory, anti-cancer, hepatoprotective, anti-diabetic, neuroprotective, and anti-angiogenic activity. In the present study, several bioactive compounds, including palmitic acid ethyl ester and linoleic acid, were identified in Phellinus linteus. The intermediate-conductance calcium-activated potassium channel (IKCa) plays an important role in the regulation of the vascular smooth muscle cells’ (VSMCs) contraction and relaxation. The activation of the IKCa channel causes the hyperpolarization and relaxation of VSMCs. To examine whether Phellinus linteus extract causes vasodilation in the mesenteric arteries of rats, we measured the isometric tension using a wire myograph. After the arteries were pre-contracted with U46619 (a thromboxane analogue, 1 µM), Phellinus linteus extract was administered. The Phellinus linteus extract induced vasodilation in a dose-dependent manner, which was independent of the endothelium. To further investigate the mechanism, we used the non-selective K+ channel blocker tetraethylammonium (TEA). TEA significantly abolished Phellinus linteus extract-induced vasodilation. Thus, we tested three different types of K+ channel blockers: iberiotoxin (BKca channel blocker), apamin (SKca channel blocker), and charybdotoxin (IKca channel blocker). Charybdotoxin significantly inhibited Phellinus linteus extract-induced relaxation, while there was no effect from apamin and iberiotoxin. Membrane potential was measured using the voltage-sensitive dye bis-(1,3-dibutylbarbituric acid)-trimethine oxonol (DiBAC4(3)) in the primary isolated vascular smooth muscle cells (VSMCs). We found that the Phellinus linteus extract induced hyperpolarization of VSMCs, which is associated with a reduced phosphorylation level of 20 KDa myosin light chain (MLC20).

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“…However, these treatment avenues often offer minimal relief and accompany a host of undesired side-effects (3,65). Since BK channels are ubiquitously expressed in a variety of tissues, including the circulatory system, pharmacologically targeting BK channels directly may also result in severe side-effects (66). In contrast, ER stress modulators like 4-PBA and AMG44 can alleviate ER stress and normalize BK channel properties, ameliorating pain and limiting the chances for adverse side-effects ( Fig.…”

Section: Discussionmentioning

confidence: 99%

ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

Yousuf¹,

Samtleben²,

Lamothe

et al. 2020

Preprint

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AcknowledgementsWe would like to thank Drs. Simonetta Sipione, Christine Webber, and Jason Plemel (University of Alberta) for graciously sharing select equipment and software. ABSTRACTNeuropathic pain is a common symptom of multiple sclerosis (MS) and current treatment options are ineffective. In this study, we investigated whether endoplasmic reticulum (ER) stress in dorsal root ganglia (DRG) contributes to pain hypersensitivity in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Inflammatory cells and increased levels of ER stress markers are evident in post-mortem DRGs from MS patients. Similarly, we observed ER stress in the DRG of mice with EAE and relieving ER stress with a chemical chaperone, 4phenylbutyric acid (4-PBA), reduced pain hypersensitivity. In vitro, 4-PBA and the selective PERK inhibitor, AMG44, normalize cytosolic Ca 2+ transients in putative DRG nociceptors. We went to assess disease-mediated changes in the functional properties of Ca 2+ -sensitive BK-type K + channels in DRG neurons. We found that the conductance-voltage (GV) relationship of BK channels was shifted to a more positive voltage, together with a more depolarized resting membrane potential in EAE cells. Our results suggest that ER stress in sensory neurons of MS patients and mice with EAE is a source of pain and that ER stress modulators can effectively counteract this phenotype.

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Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

Cited by 101 publications

References 252 publications

Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons

Slowing of the Time Course of Acidification Decreases the Acid-Sensing Ion Channel 1a Current Amplitude and Modulates Action Potential Firing in Neurons

Vasodilatory Effect of Phellinus linteus Extract in Rat Mesenteric Arteries

ER stress-mediated BK dysfunction in the DRG underlies pain in a model of multiple sclerosis

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