Gamma Oscillations and Potassium Channel Modulation in Schizophrenia: Targeting GABAergic Dysfunction.

Impairments in gamma-aminobutyric acid (GABAergic) interneuron function lead to gamma power abnormalities and are thought to underlie symptoms in people with schizophrenia. Voltage-gated potassium 3.1 (Kv3.1) and 3.2 (Kv3.2) channels on GABAergic interneurons are critical to the generation of gamma oscillations suggesting that targeting Kv3.1/3.2 could augment GABAergic function and modulate gamma oscillation generation. Here, we studied the effect of a novel potassium Kv3.1/3.2 channel modulator, AUT00206, on resting state frontal gamma power in people with schizophrenia. We found a significant positive correlation between frontal resting gamma (35-45 Hz) power (n = 22, r = 0.613, P < .002) and positive and negative syndrome scale (PANSS) positive symptom severity. We also found a significant reduction in frontal gamma power (t13 = 3.635, P = .003) from baseline in patients who received AUT00206. This provides initial evidence that the Kv3.1/3.2 potassium channel modulator, AUT00206, may address gamma oscillation abnormalities in schizophrenia.

Metabolically regulated spiking could serve neuronal energy homeostasis and protect from reactive oxygen species.

So-called spontaneous activity is a central hallmark of most nervous systems. Such non-causal firing is contrary to the tenet of spikes as a means of communication, and its purpose remains unclear. We propose that self-initiated firing can serve as a release valve to protect neurons from the toxic conditions arising in mitochondria from lower-than-baseline energy consumption. To demonstrate the viability of our hypothesis, we built a set of models that incorporate recent experimental results indicating homeostatic control of metabolic products-Adenosine triphosphate (ATP), adenosine diphosphate (ADP), and reactive oxygen species (ROS)-by changes in firing. We explore the relationship of metabolic cost of spiking with its effect on the temporal patterning of spikes and reproduce experimentally observed changes in intrinsic firing in the fruitfly dorsal fan-shaped body neuron in a model with ROS-modulated potassium channels. We also show that metabolic spiking homeostasis can produce indefinitely sustained avalanche dynamics in cortical circuits. Our theory can account for key features of neuronal activity observed in many studies ranging from ion channel function all the way to resting state dynamics. We finish with a set of experimental predictions that would confirm an integrated, crucial role for metabolically regulated spiking and firmly link metabolic homeostasis and neuronal function.

Spinal cord injury significantly alters the properties of reticulospinal neurons: delayed repolarization mediated by potassium channels.

After rostral spinal cord injury (SCI) of lampreys, the descending axons of injured (axotomized) reticulospinal (RS) neurons regenerate and locomotor function gradually recovers. Our previous studies indicated that relative to uninjured lamprey RS neurons, injured RS neurons display several dramatic changes in their biophysical properties, called the "injury phenotype." In the present study, at the onset of applied depolarizing current pulses for membrane potentials below as well as above threshold for action potentials (APs), injured RS neurons displayed a transient depolarization consisting of an initial depolarizing component followed by a delayed repolarizing component. In contrast, for uninjured neurons the transient depolarization was mostly only evident at suprathreshold voltages when APs were blocked. For injured RS neurons, the delayed repolarizing component resisted depolarization to threshold and made these neurons less excitable than uninjured RS neurons. After block of voltage-gated sodium and calcium channels for injured RS neurons, the transient depolarization was still present. After a further block of voltage-gated potassium channels, the delayed repolarizing component was abolished or significantly reduced, with little or no effect on the initial depolarizing component. Voltage-clamp experiments indicated that the delayed repolarizing component was due to a noninactivating outward-rectifying potassium channel whose conductance (gK) was significantly larger for injured RS neurons compared to that for uninjured neurons. Thus, SCI results in an increase in gK and other changes in the biophysical properties of injured lamprey RS neurons that lead to a reduction in excitability, which is proposed to create an intracellular environment that supports axonal regeneration.NEW & NOTEWORTHY After spinal cord injury (SCI), lamprey reticulospinal (RS) neurons responded to subthreshold depolarizing current pulses with a transient depolarization, which included an initial depolarization that was due to passive channels followed by a delayed repolarization that was mediated by voltage-gated potassium channels. The conductance of these channels (gK) was significantly increased for RS neurons after SCI and contributed to a reduction in excitability, which is expected to provide supportive conditions for subsequent axonal regeneration.

Single-compartment model of a pyramidal neuron, fitted to recordings with current and conductance injection.

For single neuron models, reproducing characteristics of neuronal activity such as the firing rate, amplitude of spikes, and threshold potentials as functions of both synaptic current and conductance is a challenging task. In the present work, we measure these characteristics of regular spiking cortical neurons using the dynamic patch-clamp technique, compare the data with predictions from the standard Hodgkin-Huxley and Izhikevich models, and propose a relatively simple five-dimensional dynamical system model, based on threshold criteria. The model contains a single sodium channel with slow inactivation, fast activation and moderate deactivation, as well as, two fast repolarizing and slow shunting potassium channels. The model quantitatively reproduces characteristics of steady-state activity that are typical for a cortical pyramidal neuron, namely firing rate not exceeding 30 Hz; critical values of the stimulating current and conductance which induce the depolarization block not exceeding 80 mV and 3, respectively (both values are scaled by the resting input conductance); extremum of hyperpolarization close to the midpoint between spikes. The analysis of the model reveals that the spiking regime appears through a saddle-node-on-invariant-circle bifurcation, and the depolarization block is reached through a saddle-node bifurcation of cycles. The model can be used for realistic network simulations, and it can also be implemented within the so-called mean-field, refractory density framework.

Ultrasound-Induced Membrane Hyperpolarization in Motor Axons and Muscle Fibers of the Crayfish Neuromuscular Junction.

OBJECTIVE: Focused ultrasound (FUS) can modulate neuronal activity by depolarization or hyperpolarization. Although FUS-evoked depolarization has been studied extensively, the mechanisms underlying FUS-evoked hyperpolarization (FUSH) have received little attention. In the study described here, we developed a procedure using FUS to selectively hyperpolarize motor axons in crayfish. As a previous study had reported that these axons express mechano- and thermosensitive two-pore domain potassium (K2P) channels, we tested the hypothesis that K2P channels underlie FUSH. METHODS: Intracellular recordings from a motor axon and a muscle fiber were obtained simultaneously from the crayfish opener neuromuscular preparation. FUSH was examined while K2P channel activities were modulated by varying temperature or by K2P channel blockers. RESULTS: FUSH in the axons did not exhibit a coherent temperature dependence, consistent with predicted K2P channel behavior, although changes in the resting membrane potential of the same axons indicated well-behaved K2P channel temperature dependence. The same conclusion was supported by pharmacological data; namely, FUSH was not suppressed by K2P channel blockers. Comparison between the FUS-evoked responses recorded in motor axons and muscle fibers revealed that the latter exhibited very little FUSH, indicating that the FUSH was specific to the axons. CONCLUSION: It is not likely that K2P channels are the underlying mechanism for FUSH in motor axons. Alternative mechanisms such as sonophore and axon-specific potassium channels were considered. Although the sonophore hypothesis could account for electrophysiological features of axonal recordings, it is not consistent with the lack of FUSH in muscle fibers. An axon-specific and mechanosensitive potassium channel is also a possible explanation.

KCa 2.2 (KCNN2): A physiologically and therapeutically important potassium channel.

One group of the K+ ion channels, the small-conductance Ca2+ -activated potassium channels (KCa 2.x, also known as SK channels family), is widely expressed in neurons as well as the heart, endothelial cells, etc. They are named small-conductance Ca2+ -activated potassium channels (SK channels) due to their comparatively low single-channel conductance of about ~10 pS. These channels are insensitive to changes in membrane potential and are activated solely by rises in the intracellular Ca2+ . According to the phylogenic research done on the KCa 2.x channels family, there are three channels' subtypes: KCa 2.1, KCa 2.2, and KCa 2.3, which are encoded by KCNN1, KCNN2, and KCNN3 genes, respectively. The KCa 2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. KCa 2.x channels inhibit excitatory postsynaptic potentials (EPSPs) in neuronal dendrites and contribute to the medium afterhyperpolarization (mAHP) that follows the action potential bursts. Multiple brain regions, including the hippocampus, express the KCa 2.2 channel encoded by the KCNN2 gene on chromosome 5. Of particular interest, rat cerebellar Purkinje cells express KCa 2.2 channels, which are crucial for various cellular processes during development and maturation. Patients with a loss-of-function of KCNN2 mutations typically exhibit extrapyramidal symptoms, cerebellar ataxia, motor and language developmental delays, and intellectual disabilities. Studies have revealed that autosomal dominant neurodevelopmental movement disorders resembling rodent symptoms are caused by heterozygous loss-of-function mutations, which are most likely to induce KCNN2 haploinsufficiency. The KCa 2.2 channel is a promising drug target for spinocerebellar ataxias (SCAs). SCAs exhibit the dysregulation of firing in cerebellar Purkinje cells which is one of the first signs of pathology. Thus, selective KCa 2.2 modulators are promising potential therapeutics for SCAs.

Dilation of porcine retinal arterioles to nobiletin, a polymethoxyflavonoid: Roles of nitric oxide and voltage-dependent potassium channel.

We examined the effects of nobiletin, a polymethoxyflavonoid, on the retinal microvascular diameter to determine if they depend on the endothelium and/or smooth muscle to reveal the signaling mechanisms involved in this vasomotor activity. Porcine retinal arterioles were isolated, cannulated, and pressurized without flow in vitro. Video microscopic techniques recorded diametric responses to nobiletin. The retinal arterioles dilated in a nobiletin concentration-dependent (100 pM-10 µM) manner and decreased by 50% after endothelial removal. The nitric oxide (NO) synthase inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME), reduced nobiletin-induced vasodilation comparable to denudation. Blockade of soluble guanylyl cyclase by 1H-[1,2,4] oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) produced a similar inhibitory effect as that by L-NAME. Nobiletin-induced vasodilation was also inhibited by the nonselective potassium channel inhibitor, tetraethylammonium (TEA), and the voltage-gated K (Kv) inhibitor, 4-aminopyridine. Co-administration of L-NAME and TEA almost eliminated nobiletin-induced vasodilation. Nobiletin elicits both endothelium-dependent and -independent dilation of retinal arterioles mediated by NO release and Kv channel activation, respectively.

Potassium channel modulators and schizophrenia: an overview of investigational drugs.

INTRODUCTION: Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine receptor but are largely ineffective at treating negative and cognitive symptoms. Alternative pharmacologic options that do not act directly on the dopamine receptor are being investigated, including potassium channel modulators. It has been hypothesized that dysfunctional fast-spiking parvalbumin-positive GABA interneurons, regulated by Kv3.1 and Kv3.2 potassium channels, contribute to the symptoms of schizophrenia, making potassium channels an area of clinical interest. AREAS COVERED: This review will highlight potassium channel modulators for the treatment of schizophrenia, with a focus on AUT00206. Background on Kv3.1 and Kv3.2 potassium channels will be explored. Our search strategy included a literature review utilizing PubMed, Clinicaltrials.gov, and sources available on the manufacturer's website. EXPERT OPINION: Initial data on potassium channel modulators is promising; however, further study is needed, and existing evidence is limited. Early data suggests that dysfunctional GABA interneurons can be ameliorated through modulators of Kv3.1 and Kv3.2 channels. AUT00206 has been shown to improve dopaminergic dysfunction induced by ketamine and PCP, improve resting gamma power in patients with schizophrenia, impact dopamine synthesis capacity in a subgroup of individuals with schizophrenia, and affect reward anticipation-related neural activation.

About hysteresis in Shaker: Response to note by Villalba-Galea.

In this issue, Villalba-Galea (2023. J. Gen. Physiol.https://doi.org/10.1085/jgp.202313371) expresses interest in our recently published work (Cowgill and Chanda. 2023. J. Gen. Physiol.https://doi.org/10.1085/jgp.202112883). Our response points out the deficiencies in the alternative explanation proposed by Villalba-Galea to account for our findings on hysteresis (or lack thereof) in steady state charge-voltage curves of Shaker potassium channel.

Retinal Dysfunction in a Mouse Model of HCN1 Genetic Epilepsy.

Pathogenic variants in HCN1 are associated with a range of epilepsy syndromes including a developmental and epileptic encephalopathy. The recurrent de novo HCN1 pathogenic variant (M305L) results in a cation leak, allowing the flux of excitatory ions at potentials where the wild-type channels are closed. The Hcn1M294L mouse recapitulates patient seizure and behavioral phenotypes. As HCN1 channels are highly expressed in rod and cone photoreceptor inner segments, where they shape the light response, mutated channels are likely to impact visual function. Electroretinogram (ERG) recordings from male and female mice Hcn1M294L mice revealed a significant decrease in the photoreceptor sensitivity to light, as well as attenuated bipolar cell (P2) and retinal ganglion cell responses. Hcn1M294L mice also showed attenuated ERG responses to flickering lights. ERG abnormalities are consistent with the response recorded from a single female human subject. There was no impact of the variant on the structure or expression of the Hcn1 protein in the retina. In silico modeling of photoreceptors revealed that the mutated HCN1 channel dramatically reduced light-induced hyperpolarization, resulting in more Ca2+ flux during the response when compared with the wild-type situation. We propose that the light-induced change in glutamate release from photoreceptors during a stimulus will be diminished, significantly blunting the dynamic range of this response. Our data highlight the importance of HCN1 channels to retinal function and suggest that patients with HCN1 pathogenic variants are likely to have a dramatically reduced sensitivity to light and a limited ability to process temporal information.SIGNIFICANCE STATEMENT Pathogenic variants in HCN1 are emerging as an important cause of catastrophic epilepsy. HCN1 channels are ubiquitously expressed throughout the body, including the retina. Electroretinogram recordings from a mouse model of HCN1 genetic epilepsy showed a marked decrease in the photoreceptor sensitivity to light and a reduced ability to respond to high rates of light flicker. No morphologic deficits were noted. Simulation data suggest that the mutated HCN1 channel blunts light-induced hyperpolarization and consequently limits the dynamic range of this response. Our results provide insights into the role HCN1 channels play in retinal function as well as highlighting the need to consider retinal dysfunction in disease caused by HCN1 variants. The characteristic changes in the electroretinogram open the possibility of using this tool as a biomarker for this HCN1 epilepsy variant and to facilitate development of treatments.

Glibenclamide Posttreatment Does Not Inhibit Levcromakalim Induced Headache in Healthy Participants: A Randomized Clinical Trial.

Intravenous infusion of ATP-sensitive potassium channel (KATP) opener levcromakalim causes headache in humans and implicates KATP channels in headache pathophysiology. Whether KATP channel blocker glibenclamide inhibits levcromakalim-induced headache has not yet been elucidated. We aimed to investigate the effect of posttreatment with glibenclamide on levcromakalim-induced headache in healthy participants. In a double blind, randomized, three-arm, placebo-controlled, crossover study, 20 healthy participants were randomized to receive 20 mL of levcromakalim (0.05 mg/min (50 mg/mL)) or 20 mL placebo (isotonic saline) intravenously over 20 min followed by oral administration of 10 mg glibenclamide or placebo. Fifteen participants completed all three study days. The primary endpoint was the difference in incidence of headache (0-12 h) between glibenclamide and placebo. More participants developed headache on levcromakalim-placebo day (15/15, 100%) (P = 0.013) and levcromakalim-glibenclamide day (13/15, 86%) compared to placebo-placebo day (7/15, 46%) (P = 0.041). We found no difference in headache incidence between levcromakalim-placebo day and levcromakalim-glibenclamide day (P = 0.479). The AUC0-12 h for headache intensity was significantly larger in levcromakalim-placebo day and levcromakalim-glibenclamide day compared to placebo-placebo day (106.3 ± 215.8) (P < 0.01). There was no difference in the AUC0-12 h for headache intensity between the levcromakalim-placebo day (494 ± 336.6) and the levcromakalim-glibenclamide day (417 ± 371.6) (P = 0.836). We conclude that non-specific KATP channel inhibitor glibenclamide did not attenuate levcromakalim-induced headache in healthy volunteers. Future studies should clarify the involvement of the distinct isoforms of sulfonylurea receptor subunits of KATP channels in the pathogenesis of headache and migraine.

Flavonoids as Modulators of Potassium Channels.

Potassium channels are widely distributed integral proteins responsible for the effective and selective transport of K+ ions through the biological membranes. According to the existing structural and mechanistic differences, they are divided into several groups. All of them are considered important molecular drug targets due to their physiological roles, including the regulation of membrane potential or cell signaling. One of the recent trends in molecular pharmacology is the evaluation of the therapeutic potential of natural compounds and their derivatives, which can exhibit high specificity and effectiveness. Among the pharmaceuticals of plant origin, which are potassium channel modulators, flavonoids appear as a powerful group of biologically active substances. It is caused by their well-documented anti-oxidative, anti-inflammatory, anti-mutagenic, anti-carcinogenic, and antidiabetic effects on human health. Here, we focus on presenting the current state of knowledge about the possibilities of modulation of particular types of potassium channels by different flavonoids. Additionally, the biological meaning of the flavonoid-mediated changes in the activity of K+ channels will be outlined. Finally, novel promising directions for further research in this area will be proposed.

Nicorandil Suppresses Ischemia-Induced Norepinephrine Release and Ventricular Arrhythmias in Hypertrophic Hearts.

PURPOSE: Ventricular arrhythmias (VAs) are a common cause of sudden death in acute myocardial infarction (MI), for which hypertension is a major risk factor. Nicorandil opens ATP-sensitive potassium (KATP) channels, which are expressed by nerve terminals and cardiomyocytes and regulate the release of norepinephrine (NE). However, the effects of nicorandil on ischemic NE release in cardiac tissue remain unclear. Therefore, we herein investigated whether nicorandil suppressed interstitial NE concentrations and VAs during acute MI in pressure overload-induced hypertrophic hearts. METHODS: Rats were divided into two groups: an abdominal aortic constriction (AAC) group and sham-operated (Sham) group. Four weeks after constriction, cardiac geometry and functions were examined using echocardiography and hemodynamic analyses. Myocardial ischemia was induced by coronary artery occlusion for 100 min with or without the administration of nicorandil. VAs were assessed by electrocardiography, and NE concentrations in the ischemic region were measured using a micro-dialysis method. RESULTS: AAC induced left ventricular hypertrophy with diastolic dysfunction. VAs markedly increased in the early phase (0-20 min) of ischemia in both groups and were more frequent in the AAC group. Cardiac interstitial NE concentrations were higher in the AAC group before ischemia and significantly increased during ischemia in both groups. Nicorandil significantly suppressed ischemia-induced VAs and NE increases in the AAC group. CONCLUSION: Ischemia-induced VAs were more frequent in hypertrophic hearts and associated with high interstitial concentrations of NE. The attenuation of ischemia-induced increases in NE through neuronal KATP opening by nicorandil may suppress ischemia-induced VAs in hypertrophic hearts.

Rosa damascena Miller essential oil relaxes rat trachea via K&lt;sub&gt;V&lt;/sub&gt; channels, K&lt;sub&gt;ATP&lt;/sub&gt; channels, and BK&lt;sub&gt;Ca&lt;/sub&gt; channels.

AIM/OBJECTIVE: This study aimed to investigate the effects of Rosa damascena Miller essential oil on rat tracheal smooth muscle contractility and the hypothesis that voltage-gated potassium (K&lt;sub&gt;V&lt;/sub&gt;) channels, ATP-sensitive potassium (K&lt;sub&gt;ATP&lt;/sub&gt;) channels, and large-conductance calcium-activated potassium (BK&lt;sub&gt;Ca&lt;/sub&gt;) channels may have roles in these effects. METHODS: Isometric contraction-relaxation responses of tracheal rings were measured with an isolated tissue bath model. The steady contraction was induced with both 10&lt;sup&gt;-5&lt;/sup&gt; M ACh and 60 mM KCl, and then the concentration-dependent responses of rose oil (0.1-100 µg/mL) were examined. The time-matched control (double distilled water) group was also formed. To evaluate the role of K&lt;sub&gt;V&lt;/sub&gt;, K&lt;sub&gt;ATP&lt;/sub&gt;, and BK&lt;sub&gt;Ca&lt;/sub&gt; channels, tracheal rings were incubated with 4-AP (K&lt;sub&gt;V&lt;/sub&gt; channel blocker), glibenclamide (K&lt;sub&gt;ATP&lt;/sub&gt; channel blocker), TEA (BK&lt;sub&gt;Ca&lt;/sub&gt; channel blocker), and iberiotoxin (selective BK&lt;sub&gt;Ca&lt;/sub&gt; channel blocker). Also, a vehicle control group was formed for dimethyl sulfoxide (DMSO). RESULTS: Rose oil exerted the relaxant effects in tracheal rings pre-contracted with both ACh and KCl at concentrations of 1, 10, and 100 µg/mL (p &amp;lt; 0.05). Besides, K&lt;sub&gt;V&lt;/sub&gt; channel blocker 4-AP, K&lt;sub&gt;ATP&lt;/sub&gt; channel blocker glibenclamide, and BK&lt;sub&gt;Ca&lt;/sub&gt; channel blockers TEA and iberiotoxin incubations significantly inhibited the rose oil-induced relaxation responses (p &amp;lt; 0.05). However, incubation of tissues with DMSO, glibenclamide solvent, for 10 min did not cause a significant change in the relaxation responses to rose oil (p &amp;gt; 0.05). CONCLUSIONS: In conclusion, the first physiological findings were obtained regarding the functional relaxant effects of rose essential oil in rat trachea. The findings showed that rose oil induces bronchorelaxation in a concentration-dependent manner. Besides, this study is the first to report that rose oil-mediated bronchodilation responses are associated with the activity of K&lt;sub&gt;V&lt;/sub&gt;, K&lt;sub&gt;ATP&lt;/sub&gt;, and BK&lt;sub&gt;Ca&lt;/sub&gt; channels. These results suggest that rose oil might be a useful agent in the treatment of abnormal bronchoconstriction-related diseases such as asthma and chronic obstructive pulmonary disease.

A Window to the Potassium World. The Evidence of Potassium Energetics in the Mitochondria and Identity of the Mitochondrial ATP-Dependent K+ Channel.

The conclusions made in the three papers published in Function by Juhaszova et al. [Function, 3, 2022, zqab065, zqac001, zqac018], can be seen as a breakthrough in bioenergetics and mitochondrial medicine. For more than half a century, it has been believed that mitochondrial energetics is solely protonic and is based on the generation of electrochemical potential of hydrogen ions across the inner mitochondrial membrane upon oxidation of respiratory substrates, resulting in the generation of ATP via reverse transport of protons through the ATP synthase complex. Juhaszova et al. demonstrated that ATP synthase transfers not only protons, but also potassium ions, with the generation of ATP. This mechanism seems logical, given the fact that in eukaryotic cells, the concentration of potassium ions is several million times higher than the concentration of protons. The transport of K+ through the ATP synthase was enhanced by the activators of mitochondrial ATP-dependent K+ channel (mK/ATP), leading to the conclusion that ATP synthase is the material essence of mK/ATP. Beside ATP generation, the transport of osmotically active K+ to the mitochondrial matrix is accompanied by water entry to the matrix, leading to an increase in the matrix volume and activation of mitochondrial respiration with the corresponding increase in the ATP synthesis, which suggests an advantage of such transport for energy production. The driving force for K+ transport into the mitochondria is the membrane potential; an excess of K+ is exported from the matrix by the hypothetical K+/H+ exchangers. Inhibitory factor 1 (IF1) plays an important role in the activation of mK/ATP by increasing the chemo-mechanical efficiency of ATP synthase, which may be a positive factor in the protective anti-ischemic signaling.

Irisin Relaxes Rat Trachea via KV Channels, KATP Channels, and BKCa Channels.

BACKGROUND: This study aimed to investigate the effects of irisin on rat tracheal smooth muscle contraction-relaxation responses and the roles of voltage-gated potassium (KV) channels, ATP-sensitive potassium (KATP) channels, and large-conductance calcium-activated potassium (BKCa) channels in these effects. METHODS: Isometric contraction and relaxation responses of tracheal segments were measured using the tissue bath method. Submaximal contractions were induced by ACh (10-5 M) or KCl (60 mM), and then concentration-response curves of irisin (10-9 to 10-6 M) were obtained. For the temporal control, a double-distilled water group was formed. ACh and irisin were added to the baths after tracheal segments were incubated with 4-AP (KV channel blocker), glibenclamide (KATP channel blocker), TEA, and iberiotoxin (BKCa channel blockers) to assess the role of K+ channels. In addition, a vehicle group was performed for the solvent dimethyl sulfoxide (DMSO). RESULTS: Irisin exhibited the relaxant effects in tracheal segments precontracted with both ACh and KCl at concentrations of 10-8-10-6 M (p<0.05). Besides, incubations of 4-AP, glibenclamide, TEA, and iberiotoxin significantly inhibited the irisin-mediated relaxation (p<0.05), whereas DMSO incubation did not modulate irisin responses (p>0.05). CONCLUSION: In conclusion, the first physiological results on the relaxant effects of irisin in rat trachea were obtained. Our findings demonstrated that irisin mediates concentration-dependent relaxation in rat tracheas. Moreover, the present study reported for the first time that irisin-induced bronchorelaxation is associated with the activity of the K+ channels.

Cellular mechanisms underlying state-dependent neural inhibition with magnetic stimulation.

Novel stimulation protocols for neuromodulation with magnetic fields are explored in clinical and laboratory settings. Recent evidence suggests that the activation state of the nervous system plays a significant role in the outcome of magnetic stimulation, but the underlying cellular and molecular mechanisms of state-dependency have not been completely investigated. We recently reported that high frequency magnetic stimulation could inhibit neural activity when the neuron was in a low active state. In this paper, we investigate state-dependent neural modulation by applying a magnetic field to single neurons, using the novel micro-coil technology. High frequency magnetic stimulation suppressed single neuron activity in a state-dependent manner. It inhibited neurons in slow-firing states, but spared neurons from fast-firing states, when the same magnetic stimuli were applied. Using a multi-compartment NEURON model, we found that dynamics of voltage-dependent sodium and potassium channels were significantly altered by the magnetic stimulation in the slow-firing neurons, but not in the fast-firing neurons. Variability in neural activity should be monitored and explored to optimize the outcome of magnetic stimulation in basic laboratory research and clinical practice. If selective stimulation can be programmed to match the appropriate neural state, prosthetic implants and brain-machine interfaces can be designed based on these concepts to achieve optimal results.

Kv Channel Ancillary Subunits: Where Do We Go from Here?

Voltage-gated potassium (Kv) channels each comprise four pore-forming α-subunits that orchestrate essential duties such as voltage sensing and K+ selectivity and conductance. In vivo, however, Kv channels also incorporate regulatory subunits-some Kv channel specific, others more general modifiers of protein folding, trafficking, and function. Understanding all the above is essential for a complete picture of the role of Kv channels in physiology and disease.

Positive rate-dependent action potential prolongation by modulating potassium ion channels.

Pharmacological agents that prolong action potential duration (APD) to a larger extent at slow rates than at the fast excitation rates typical of ventricular tachycardia exhibit reverse rate dependence. Reverse rate dependence has been linked to the lack of efficacy of class III agents at preventing arrhythmias because the doses required to have an antiarrhythmic effect at fast rates may have pro-arrhythmic effects at slow rates due to an excessive APD prolongation. In this report, we show that, in computer models of the ventricular action potential, APD prolongation by accelerating phase 2 repolarization (by increasing IKs ) and decelerating phase 3 repolarization (by blocking IKr and IK1 ) results in a robust positive rate dependence (i.e., larger APD prolongation at fast rates than at slow rates). In contrast, APD prolongation by blocking a specific potassium channel type results in reverse rate dependence or a moderate positive rate dependence. Interventions that result in a strong positive rate dependence tend to decrease the repolarization reserve because they require substantial IK1 block. However, limiting IK1 block to ~50% results in a strong positive rate dependence with moderate decrease in repolarization reserve. In conclusion, the use of a combination of IKs activators and IKr and IK1 blockers could result in APD prolongation that potentially maximizes antiarrhythmic effects (by maximizing APD prolongation at fast excitation rates) and minimizes pro-arrhythmic effects (by minimizing APD prolongation at slow excitation rates).