Calcium-activated Potassium Current Research Articles

Potassium Current Signature of Neuronal/Glial Progenitors in Amniotic Fluid Stem Cells.

Amniotic fluid is a complex and dynamic biological matrix that surrounds the fetus during the pregnancy. From this fluid, is possible to isolate various cell types with particular interest directed towards stem cells (AF-SCs). These cells are highly appealing due to their numerous potential applications in the field of regenerative medicine for tissues and organs as well as for treating conditions such as traumatic or ischemic injuries to the nervous system, myocardial infarction, or cancer. AF-SCs, when subcultured in the presence of basic Fibroblast Growth Factor (bFGF), have been shown to survive and migrate when transplanted into the striatum of the rat brain, exhibiting behavior characteristics of neuronal/glial progenitor cells. In this work, we performed an electrophysiological characterization to ascertain the propensity of AF-SCs to differentiate into glial and neuronal cells by bFGF. By using patch clamp technique we characterized a fibroblast-like morphology that display a barium-sensitive inward-rectifying potassium current (Kir) and calcium-activated potassium currents (KCa). The electrophysiological and calcium dynamics of histamine, a marker of undifferentiated neural progenitors, was further studied. Histamine promoted intracellular calcium increase by Fura-2 recording and calcium-activated potassium current activation with a similar temporal profile in AF-SC. The data presented in this paper ultimately confirm the expression in AF-SCs of the Kir and KCa currents, also showing regulation by endogenous stimuli such as histamine for the latter.

Acacetin is a Promising Drug Candidate for Cardiovascular Diseases.

Phytochemical flavonoids have been proven to be effective in treating various disorders, including cardiovascular diseases. Acacetin is a natural flavone with diverse pharmacological effects, uniquely including atrial-selective anti-atrial fibrillation (AF) via the inhibition of the atrial specific potassium channel currents [Formula: see text] (ultra-rapidly delayed rectifier potassium current), [Formula: see text] (acetylcholine-activated potassium current), [Formula: see text] (calcium-activated small conductance potassium current), and [Formula: see text] (transient outward potassium current). [Formula: see text] inhibition by acacetin, notably, suppresses experimental J-wave syndromes. In addition, acacetin provides extensive cardiovascular protection against ischemia/reperfusion injury, cardiomyopathies/heart failure, autoimmune myocarditis, pulmonary artery hypertension, vascular remodeling, and atherosclerosis by restoring the downregulated intracellular signaling pathway of Sirt1/AMPK/PGC-1α followed by increasing Nrf2/HO-1/SOD thereby inhibiting oxidation, inflammation, and apoptosis. This review provides an integrated insight into the capabilities of acacetin as a drug candidate for treating cardiovascular diseases, especially atrial fibrillation and cardiomyopathies/heart failure.

Up-regulated small-conductance calcium-activated potassium currents contribute to atrial arrhythmogenesis in high-fat feeding mice.

Metabolic syndrome (MetS) is associated with arrhythmias and cardiovascular mortality. Arrhythmogenesis in MetS results from atrial structural and electrical remodelling. The small-conductance Ca2+-activated K+ (SK) currents modulate atrial repolarization and may influence atrial arrhythmogenicity. This study investigated the regulation of SK current perturbed by a high-fat diet (HFD) to mimic MetS. Thirty mice were divided into two groups that were fed with normal chow (CTL) and HFD for 4 months. Electrocardiography and echocardiography were used to detect cardiac electrical and structure remodelling. Atrial action potential duration (APD) and calcium transient duration (CaTD) were measured by optical mapping of Langendorff-perfused mice hearts. Atrial fibrillation (AF) inducibility and duration were assessed by burst pacing. Whole-cell patch clamp was performed in primarily isolated atrial myocytes for SK current density. The SK current density is higher in atrial myocytes from HFD than in CTL mice (P ≤ 0.037). The RNA and protein expression of SK channels are increased in HFD mice (P ≤ 0.041 and P ≤ 0.011, respectively). Action potential duration is shortened in HFD compared with CTL (P ≤ 0.015). The shortening of the atrial APD in HFD is reversed by the application of 100 nM apamin (P ≤ 0.043). Compared with CTL, CaTD is greater in HFD atria (P ≤ 0.029). Calcium transient decay (Tau) is significantly higher in HFD than in CTL (P = 0.001). Both APD and CaTD alternans thresholds were higher in HFD (P ≤ 0.043), along with higher inducibility and longer duration of AF in HFD (P ≤ 0.023). Up-regulation of apamin-sensitive SK currents plays a partial role in the atrial arrhythmogenicity of HFD mice.

Complexity decline of hippocampal CA1 circuit model due to cholinergic deficiency associated with Alzheimer's disease.

A hallmark of Alzheimer's disease (AD) is cholinergic system dysfunction, directly affecting the hippocampal neurons. Previous experiments have demonstrated that reduced complexity is one significant effect of AD on electroencephalography (EEG). Motivated by these, this study explores reduced EEG complexity of cholinergic deficiency in AD by neurocomputation. We first construct a new hippocampal CA1 circuit model with cholinergic action. M-current and calcium-activated potassium current are newly introduced in the model to describe cholinergic input from the medial septum. Then, by enhancing and to mimic cholinergic deficiency, how cholinergic deficiency influences the model complexity is investigated by sample entropy (SampEn) and approximate entropy (ApEn). Numerical results show a more severe cholinergic deficit with lower model complexity. Furthermore, we conclude that the decline of SampEn and ApEn is due to the greatly diminished excitability of model neurons. These suggest that decreased neuronal excitability due to cholinergic impairment may contribute to reduced EEG complexity in AD. Subsequently, statistical analysis between simulated AD patients and normal control (NC) groups demonstrates that SampEn and auto-mutual-information (AMI) decrease rates significantly differ. Compared to NC, AD patients have a lower SampEn and a less negative AMI decline rate. These imply a low rate of new-generation information in AD brains with cholinergic deficits. Interestingly, the statistical correlation between SampEn and AMI is analyzed, and they have a large negative Pearson correlation coefficient. Thus, AMI reduction rates may be a complementary tool for complex analysis. Our modeling and complex analysis are expected to provide a deeper understanding of the reduced EEG complexity resulting from cholinergic deficiency.

1389-P: Asprosin-Neutralizing Antibodies as a Treatment for Binge Eating

The central nervous system (CNS) circuits that regulate binge eating remain to be identified, and effective treatments for binge eating are limited. Here, we provide evidence to support the vital role of asprosin, a novel fasting-induced glucogenic and orexigenic hormone, in the development of binge eating. We found that heterozygous deletion of fibrillin 1, the gene encoding asprosin protein, led to a 50% decrease in asprosin production and reduced binge-like eating behavior in mice. Consistently, systemic treatment of asprosin promoted, while an asprosin-neutralizing antibody inhibited, binge-like eating behavior. These behavioral changes were associated with increased or decreased activity of gamma-aminobutyric acid (GABA) producing neurons in the zona incerta (ZI) brain region, respectively. Mechanistically, we further demonstrate that asprosin stimulates ZI GABA neurons by decreasing small-conductance, calcium-activated potassium (SK) currents. Conversely, the asprosin-neutralizing antibody inhibits ZI GABA neurons by increasing SK currents. Our results support a model that asprosin decreases SK currents to stimulate ZI GABA neurons, further promoting binge-like eating behavior and causing obesity in mice. Our findings also provided preclinical evidence that asprosin-neutralizing antibodies could be used to treat binge eating. Keywords: Asprosin, neutralizing antibody, binge eating, obesity, GABA neurons Disclosure P. Xu: None. Y. He: None. Funding National Institutes of Health (P30 DK072476)

LY294002 Inhibits Intermediate Conductance Calcium-Activated Potassium (KCa3.1) Current in Human Glioblastoma Cells.

Glioblastomas (GBs) are among the most common tumors with high malignancy and invasiveness of the central nervous system. Several alterations in protein kinase and ion channel activity are involved to maintain the malignancy. Among them, phosphatidylinositol 3-kinase (PI3K) activity and intermediate conductance calcium-activated potassium (KCa3.1) current are involved in several aspects of GB biology. By using the electrophysiological approach and noise analysis, we observed that KCa3.1 channel activity is LY294002-sensitive and Wortmannin-resistant in accordance with the involvement of PI3K class IIβ (PI3KC2β). This modulation was observed also during the endogenous activation of KCa3.1 current with histamine. The principal action of PI3KC2β regulation was the reduction of open probability in intracellular free calcium saturating concentration. An explanation based on the “three-gate” model of the KCa3.1 channel by PI3KC2β was proposed. Based on the roles of KCa3.1 and PI3KC2β in GB biology, a therapeutic implication was suggested to prevent chemo- and radioresistance mechanisms.

BK in Double-Membrane Organelles: A Biophysical, Pharmacological, and Functional Survey.

In the 1970s, calcium-activated potassium currents were recorded for the first time. In 10years, this Ca2+-activated potassium channel was identified in rat skeletal muscle, chromaffin cells and characterized in skeletal muscle membranes reconstituted in lipid bilayers. This calcium- and voltage-activated potassium channel, dubbed BK for “Big K” due to its large ionic conductance between 130 and 300 pS in symmetric K+. The BK channel is a tetramer where the pore-forming α subunit contains seven transmembrane segments. It has a modular architecture containing a pore domain with a highly potassium-selective filter, a voltage-sensor domain and two intracellular Ca2+ binding sites in the C-terminus. BK is found in the plasma membrane of different cell types, the inner mitochondrial membrane (mitoBK) and the nuclear envelope’s outer membrane (nBK). Like BK channels in the plasma membrane (pmBK), the open probability of mitoBK and nBK channels are regulated by Ca2+ and voltage and modulated by auxiliary subunits. BK channels share common pharmacology to toxins such as iberiotoxin, charybdotoxin, paxilline, and agonists of the benzimidazole family. However, the precise role of mitoBK and nBK remains largely unknown. To date, mitoBK has been reported to play a role in protecting the heart from ischemic injury. At the same time, pharmacology suggests that nBK has a role in regulating nuclear Ca2+, membrane potential and expression of eNOS. Here, we will discuss at the biophysical level the properties and differences of mitoBK and nBK compared to those of pmBK and their pharmacology and function.

Post myocardial infarction ionic remodelling promotes repolarisation dispersions and abnormalities in acute and chronic stages

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Wellcome Trust Background Sudden cardiac death after a myocardial infarction (MI) was reported in both the acute stage and the chronic stage with the development of heart failure (HF). Around 50% of these deaths were due to ventricular tachyarrhythmia which is related to the temporal dispersion of repolarisation caused by the post-MI remodelling of ionic currents. While variable extent of ionic current changes was observed in multiple animal species in different post-MI phases, the proarrhythmic effects of such remodelling in post infarction human hearts is not fully explored. Purpose The goal of this study is to explore the proarrhythmic effects of post-MI ionic remodelling in human ventricular myocyte models of electrophysiology for both the acute and the chronic stages. Methods The ToR-ORd human ventricular cellular model was used as the baseline model, and a new formulation of the calcium activated potassium current was implemented. We constructed and calibrated a population of 253 human ventricular cell models (POM) to represent electrophysiological variability of normal zone (NZ) myocytes. For the acute phase, three types of border zone (BZ) remodelling (Acute BZ1-3) were introduced based on dog experimental data collected within one week after infarction. For the chronic phase with the development of HF, BZ (Chronic BZ) and one type of remote zone (RZ) remodelling (Chronic RZ1) were introduced based on minipig data collected 5 months post-MI. Another type of RZ remodelling (Chronic RZ2) was introduced based on experimental data from failing human hearts. The cellular models were paced at cycle lengths of 1000ms, 500ms, 400ms and 300ms for 500 beats before the analysis of repolarization abnormalities. Results For both the acute and the chronic stages post-MI, the extent of repolarisation dispersion between BZ and the corresponding NZ and RZ varied from 2ms up to 120ms, and largely depended on the level of potassium current remodelling. A weaker calcium transient was always observed in the BZ. Early after depolarisations (EADs) and repolarisation failure (RF) were observed in the chronic stages, caused by the reactivation of L-type calcium current due to the augmentation of late sodium current and the inhibition of hERG current. Beat-to-beat repolarization alternans was observed in both the acute and the chronic stages, with the key ionic mechanisms being the inhibition of SERCA activity and the slower calcium release due to enhanced CaMKII. Conclusions Post-MI ionic remodelling of the acute and chronic stages can cause a substantial dispersion of repolarisation in human hearts by inducing the prolongation of action potential durations, EADs, RFs, and alternans, providing substrates for the generation and maintenance of lethal reentrant waves. Abstract Figure. BZ and RZ ionic current remodelling

Simultaneous activation of the small conductance calcium-activated potassium current by acetylcholine and inhibition of sodium current by ajmaline cause J-wave syndrome in Langendorff-perfused rabbit ventricles

Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong. The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline. We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes. ACh (1 μM) + ajmaline (2 μM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former. ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles.

Effects of ondansetron on apamin-sensitive small conductance calcium-activated potassium currents in pacing-induced failing rabbit hearts

Ondansetron, a widely prescribed antiemetic, has been implicated in drug-induced long QT syndrome. Recent patch clamp experiments have shown that ondansetron inhibits the apamin-sensitive small conductance calcium-activated potassium current (IKAS). The purpose of this study was to determine whether ondansetron causes action potential duration (APD) prolongation by IKAS inhibition. Optical mapping was performed in rabbit hearts with pacing-induced heart failure (HF) and in normal hearts before and after ondansetron (100 nM) infusion. APD at 80% repolarization (APD80) and arrhythmia inducibility were determined. Additional studies with ondansetron were performed in normal hearts perfused with hypokalemic Tyrode's (2.4 mM) solution before or after apamin administration. The corrected QT interval in HF was 326 ms (95% confidence interval [CI] 306-347 ms) at baseline and 364 ms (95% CI 351-378 ms) after ondansetron infusion (P < .001). Ondansetron significantly prolonged APD80 in the HF group and promoted early afterdepolarizations, steepened the APD restitution curve, and increased ventricular vulnerability. Ventricular fibrillation was not inducible in HF ventricles at baseline, but after ondansetron infusion, ventricular fibrillation was induced in 5 of the 7 ventricles (P = .021). In hypokalemia, apamin prolonged APD80 from 163 ms (95% CI 146-180 ms) to 180 ms (95% CI 156-204 ms) (P = .018). Subsequent administration of ondansetron failed to further prolong APD80 (180 ms [95% CI 156-204 ms] vs 179 ms [95% CI 165-194 ms]; P= .789). The results were similar when ondansetron was administered first, followed by apamin. Ondansetron is a specific IKAS blocker at therapeutic concentrations. Ondansetron may prolong the QT interval in HF by inhibiting small conductance calcium-activated potassium channels, which increases the vulnerability to ventricular arrhythmias.

Repeated toluene exposure increases the excitability of layer 5 pyramidal neurons in the prefrontal cortex of adolescent rats

Despite serious health effects, volatile industrial products containing toluene are deliberately inhaled for their psychoactive actions, mainly among adolescents and young adults. Chronic toluene inhalation induces multiple alterations at the cellular and behavioral level; however, modifications of neuronal networks associated with the reward system after repeated toluene exposure are not thoroughly characterized. Here we used whole-cell recordings to determine the effects of repeated exposure to toluene (1000, 4000 or 8000 ppm for 30 min, twice a day, for ten days) on the neurophysiological properties of prelimbic layer 5 pyramidal neurons of the medial prefrontal cortex (mPFC) in adolescent male Wistar rats. Neurons from animals repeatedly exposed to toluene showed a concentration-dependent increase in action potential firing discharge. This increase was related to a reduction of the small-conductance calcium-activated potassium current (after-hyperpolarization current, IAHP) that controls the firing frequency of neurons. Likewise, toluene altered the kinetics of the action potential. The hyperexcitability seen in toluene-exposed animals was also associated with an increase in the glutamatergic spontaneous synaptic activity converging on mPFC neurons. In summary, repeated toluene exposure enhances the excitability of prelimbic layer 5 pyramidal neurons of the mPFC in adolescent rats.

Calcium-Dependent Regulation of Potassium Channels in Cardiac Electrophysiology: A Computational Study

Calcium-dependent regulation of several potassium channels has recently been identified, but its relative importance for atrial and ventricular electrophysiology, and potentially arrhythmogenesis, is incompletely understood. Here, we employed computational modeling to study calcium-dependent regulation of potassium channels in cardiac electrophysiology. Calcium-dependent regulation of the basal inward-rectifier (IK1), slow delayed-rectifier (IKs), and small-conductance calcium-activated (ISK) potassium currents was incorporated into established atrial (Grandi-Bers) and ventricular (O’Hara-Rudy) cardiomyocyte models and compared to simulations without calcium-dependent regulation. Calcium-dependent activation of IK1 and ISK shortened atrial and ventricular action potential (AP) duration (APD), but their regulation by rate-dependent intracellular calcium loading only modestly affected APD rate dependence. The impact of calcium-dependent potassium current regulation was limited because 1) IKs has a minor impact on repolarization under basal conditions and 2) calcium-dependent activation of IK1, IKs and ISK is already almost saturated at slow rates. Accordingly, after incorporating a gain-of-function mutation that increased IKs, calcium-dependent IKs activation reduced APD without modulating APD rate dependence. Furthermore, simulated L-type calcium channel inhibition lowered intracellular calcium, decreasing calcium-dependent regulation of potassium currents and significantly prolonging APD. Finally, simulated diastolic sarcoplasmic reticulum calcium releases produced delayed afterdepolarizations in the ventricular model and triggered APs in the atrial model. Calcium-dependent augmentation of potassium currents did not affect the threshold for triggered atrial APs, but significantly reduced afterdepolarization amplitude in the ventricle due to a calcium-dependent increase in IK1. This effect was not visible in the atrial model due to the smaller IK1 and the higher sensitivity for triggered APs. Taken together, physiologic calcium-dependent potassium-channel regulation has a modest impact on basal atrial and ventricular electrophysiology, but may be further enhanced during conditions of abnormal repolarization or impaired calcium handling, and as such may play a role in cardiac arrhythmogenesis.

Role of apamin-sensitive small conductance calcium-activated potassium currents in long-term cardiac memory in rabbits

Apamin-sensitive small conductance calcium-activated K current (IKAS) is up-regulated during ventricular pacing and masks short-term cardiac memory (CM). The purpose of this study was to determine the role of IKAS in long-term CM. CM was created with 3-5 weeks of ventricular pacing and defined by a flat or inverted T wave off pacing. Epicardial optical mapping was performed in both paced and normal ventricles. Action potential duration (APD80) was determined during right atrial pacing. Ventricular stability was tested before and after IKAS blockade. Four paced hearts and 4 normal hearts were used for western blotting and histology. There were no significant differences in either echocardiographic parameters or fibrosis levels between groups. Apamin induced more APD80 prolongation in CM than in normal ventricles (mean [95% confidence interval]: 9.6% [8.8%-10.5%] vs 3.1% [1.9%-4.3%]; P <.001). Apamin significantly lengthened APD80 in the CM model at late activation sites, indicating significant IKAS up-regulation at those sites. The CM model also had altered Ca2+ handling, with the 50% Ca2+ transient duration and amplitude increased at distal sites compared to a proximal site (near the pacing site). After apamin, the CM model had increased ventricular fibrillation (VF) inducibility (paced vs control: 33/40 (82.5%) vs 7/20 (35%); P <.001) and longer VF durations (124 vs 26 seconds;P<.001). Chronic ventricular pacing increases Ca2+ transients at late activation sites, which activates IKAS to maintain repolarization reserve. IKAS blockade increases VF vulnerability in chronically paced rabbit ventricles.

Postsynaptic GABA(B) Receptors Contribute to the Termination of Giant Depolarizing Potentials in CA3 Neonatal Rat Hippocampus.

During development, hippocampal CA3 network generates recurrent population bursts, so-called Giant Depolarizing Potentials (GDPs). GDPs are characterized by synchronous depolarization and firing of CA3 pyramidal cells followed by afterhyperpolarization (GDP-AHP). Here, we explored the properties of GDP-AHP in CA3 pyramidal cells using gramicidin perforated patch clamp recordings from neonatal rat hippocampal slices. We found that GDP-AHP occurs independently of whether CA3 pyramidal cells fire action potentials (APs) or remain silent during GDPs. However, the amplitude of GDP-AHP increased with the number of APs the cells fired during GDPs. The reversal potential of the GDP-AHP was close to the potassium equilibrium potential. During voltage-clamp recordings, current-voltage relationships of the postsynaptic currents activated during GDP-AHP were characterized by reversal near the potassium equilibrium potential and inward rectification, similar to the responses evoked by the GABA(B) receptor agonists. Finally, the GABA(B) receptor antagonist CGP55845 strongly reduced GDP-AHP and prolonged GDPs, eventually transforming them to the interictal and ictal-like discharges. Together, our findings suggest that the GDP-AHP involves two mechanisms: (i) postsynaptic GABA(B) receptor activated potassium currents, which are activated independently on whether the cell fires or not during GDPs; and (ii) activity-dependent, likely calcium activated potassium currents, whose contribution to the GDP-AHP is dependent on the amount of firing during GDPs. We propose that these two complementary inhibitory postsynaptic mechanisms cooperate in the termination of GDP.

P921Small-conductance calcium-activated potassium current promotes atrial fibrillation due to reginal heterogeneity in the accumulation of intracellular calcium

P921Small-conductance calcium-activated potassium current promotes atrial fibrillation due to reginal heterogeneity in the accumulation of intracellular calcium

Ionic Current Changes during Action Potentials in Porcine Post-MI Heart Failure Model

RATIONALE: Heart failure (HF) following chronic myocardial infarction (MI) is associated with increased susceptibility for cardiac arrhythmias. However, the complex electrophysiological changes causing cardiac arrhythmias remain incompletely understood, especially in large animal models. METHOD: In a porcine model of ischemic HF we used action potential (AP)-clamp and sequential dissection of the major ionic currents during the cardiac AP in ventricular myocytes (from infarct border and remote zones 5 months after MI induction). RESULTS: (1) Compared to healthy controls, remote zone myocytes exhibited increased late sodium current, calcium-activated chloride current and calcium-activated potassium current, decreased rapid delayed rectifier potassium current and also altered sodium/calcium exchange current dynamics. These changes combine to lengthen the AP duration (APD) in the remote zone. (2) In the border zone, the above changes also occurred, but with additional pronounced decreases in L-type calcium current and inward rectifier potassium current, and calcium-activated potassium current was further enhanced to become a major repolarizing current. These additional changes shortened the APD in the border zone. CONCLUSIONS: Ischemic HF involves complex changes in many ionic currents. The changes in each individual current are modest; however, the combined changes in multiple currents integrate to cause APD shortening in the border zone but APD lengthening in the remote zone. Changes in many ionic currents significantly increase the APD dispersion surrounding the infarct to provide a substrate for cardiac arrhythmias.

Role of Apamin-Sensitive Calcium-Activated Small-Conductance Potassium Currents on the Mechanisms of Ventricular Fibrillation in Pacing-Induced Failing Rabbit Hearts.

Ventricular fibrillation (VF) during heart failure is characterized by stable reentrant spiral waves (rotors). Apamin-sensitive small-conductance calcium-activated potassium currents (IKAS) are heterogeneously upregulated in failing hearts. We hypothesized that IKAS influences the location and stability of rotors during VF. Optical mapping was performed on 9 rabbit hearts with pacing-induced heart failure. The epicardial right ventricular and left ventricular surfaces were simultaneously mapped in a Langendorff preparation. At baseline and after apamin (100 nmol/L) infusion, the action potential duration (APD80) was determined, and VF was induced. Areas with a >50% increase in the maximum action potential duration (ΔAPD) after apamin infusion were considered to have a high IKAS distribution. At baseline, the distribution density of phase singularities during VF in high IKAS distribution areas was higher than in other areas (0.0035±0.0011 versus 0.0014±0.0010 phase singularities/pixel; P=0.004). In addition, high dominant frequencies also colocalized to high IKAS distribution areas (26.0 versus 17.9 Hz; P=0.003). These correlations were eliminated during VF after apamin infusion, as the number of phase singularities (17.2 versus 11.0; P=0.009) and dominant frequencies (22.1 versus 16.2 Hz; P=0.022) were all significantly decreased. In addition, reentrant spiral waves became unstable after apamin infusion, and the duration of VF decreased. The IKAS current influences the mechanism of VF in failing hearts as phase singularities, high dominant frequencies, and reentrant spiral waves all correlated to areas of high IKAS. Apamin eliminated this relationship and reduced VF vulnerability.

BK Channels Are Required for Multisensory Plasticity in the Oculomotor System

Neural circuits are endowed with several forms of intrinsic and synaptic plasticity that could contribute to adaptive changes in behavior, but circuit complexities have hindered linking specific cellular mechanisms with their behavioral consequences. Eye movements generated by simple brainstem circuits provide a means for relating cellular plasticity to behavioral gain control. Here we show that firing rate potentiation, a form of intrinsic plasticity mediated by reductions in BK-type calcium-activated potassium currents in spontaneously firing neurons, is engaged during optokinetic reflex compensation for inner ear dysfunction. Vestibular loss triggers transient increases in postsynaptic excitability, occlusion of firing rate potentiation, and reductions in BKcurrents in vestibular nucleus neurons. Concurrently, adaptive increases in visually evoked eye movements rapidly restore oculomotor function in wild-type mice but are profoundly impaired in BK channel-null mice. Activity-dependent regulation of intrinsic excitability may be a general mechanism for adaptive control of behavioral output in multisensory circuits.

A leaky integrate-and-fire model with adaptation for the generation of a spike train.

A model is proposed to describe the spike-frequency adaptation observed in many neuronal systems. We assume that adaptation is mainly due to a calcium-activated potassium current, and we consider two coupled stochastic differential equations for which an analytical approach combined with simulation techniques and numerical methods allow to obtain both qualitative and quantitative results about asymptotic mean firing rate, mean calcium concentration and the firing probability density. A related algorithm, based on the Hazard Rate Method, is also devised and described.

Transient BK outward current enhances motoneurone firing rates during Drosophila larval locomotion.

We combine in situ electrophysiology with genetic manipulation in Drosophila larvae aiming to investigate the role of fast calcium-activated potassium currents for motoneurone firing patterns during locomotion. We first demonstrate that slowpoke channels underlie fast calcium-activated potassium currents in these motoneurones. By conducting recordings in semi-intact animals that produce crawling-like movements, we show that slowpoke channels are required specifically in motoneurones for maximum firing rates during locomotion. Such enhancement of maximum firing rates occurs because slowpoke channels prevent depolarization block by limiting the amplitude of motoneurone depolarization in response to synaptic drive. In addition, slowpoke channels mediate a fast afterhyperpolarization that ensures the efficient recovery of sodium channels from inactivation during high frequency firing. The results of the present study provide new insights into the mechanisms by which outward conductances facilitate neuronal excitability and also provide direct confirmation of the functional relevance of precisely regulated slowpoke channel properties in motor control. A large number of voltage-gated ion channels, their interactions with accessory subunits, and their post-transcriptional modifications generate an immense functional diversity of neurones. Therefore, a key challenge is to understand the genetic basis and precise function of specific ionic conductances for neuronal firing properties in the context of behaviour. The present study identifies slowpoke (slo) as exclusively mediating fast activating, fast inactivating BK current (ICF ) in larval Drosophila crawling motoneurones. Combining in vivo patch clamp recordings during larval crawling with pharmacology and targeted genetic manipulations reveals that ICF acts specifically in motoneurones to sculpt their firing patterns in response to a given input from the central pattern generating (CPG) networks. First, ICF curtails motoneurone postsynaptic depolarizations during rhythmical CPG drive. Second, ICF is activated during the rising phase of the action potential and mediates a fast afterhyperpolarization. Consequently, ICF is required for maximal intraburst firing rates during locomotion, probably by allowing recovery from inactivation of fast sodium channels and decreased potassium channel activation. This contrasts the common view that outward conductances oppose excitability but is in accordance with reports on transient BK and Kv3 channel function in multiple types of vertebrate neurones. Therefore, our finding that ICF enhances firing rates specifically during bursting patterns relevant to behaviour is probably of relevance to all brains.