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N-methyl-d-aspartate receptors (NMDARs) play a pivotal role in synaptic plasticity. While the functional role of post-synaptic NMDARs is well established, pre-synaptic NMDAR (pre-NMDAR) function is largely unexplored. Different pre-NMDAR subunit populations are documented at synapses, suggesting that subunit composition influences neuronal transmission. Here, we used electrophysiological recordings at Schaffer collateral-CA1 synapses partnered with Ca2+ imaging and glutamate uncaging at boutons of CA3 pyramidal neurones to reveal two populations of pre-NMDARs that contain either the GluN2A or GluN2B subunit. Activation of the GluN2B population decreases action potential-evoked Ca2+ influx via modulation of small-conductance Ca2+-activated K+ channels, while activation of the GluN2A population does the opposite. Critically, the level of functional expression of the subunits is subject to homeostatic regulation, bidirectionally affecting short-term facilitation, thus providing a capacity for a fine adjustment of information transfer. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

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Alzheimer's disease (AD) is a neurodegenerative disorder that is characterized by progressive impairment in cognition and memory. AD is accompanied by several neuropsychiatric symptoms, with depression being the most prominent. Although depression has long been known to be associated with AD, controversial findings from preclinical and clinical studies have obscured the precise nature of this association. However recent evidence suggests that depression could be a prodrome or harbinger of AD. Evidence indicates that the major central serotonergic nucleus-the dorsal raphe nucleus (DRN)-shows very early AD pathology: neurofibrillary tangles made of hyperphosphorylated tau protein and degenerated neurites. AD and depression share common pathophysiologies, including functional deficits of the serotonin (5-HT) system. 5-HT receptors have modulatory effects on the progression of AD pathology i.e., reduction in Aß load, increased hyper-phosphorylation of tau, decreased oxidative stress etc. Moreover, preclinical models show a role for specific channelopathies that result in abnormal regional activational and neuroplasticity patterns. One of these concerns the pathological upregulation of the small conductance calcium-activated potassium (SK) channel in corticolimbic structure. This has also been observed in the DRN in both diseases. The SKC is a key regulator of cell excitability and long-term potentiation (LTP). SKC over-expression is positively correlated with aging and cognitive decline, and is evident in AD. Pharmacological blockade of SKCs has been reported to reverse symptoms of depression and AD. Thus, aberrant SKC functioning could be related to depression pathophysiology and diverts its late-life progression towards the development of AD. We summarize findings from preclinical and clinical studies suggesting a molecular linkage between depression and AD pathology. We also provide a rationale for considering SKCs as a novel pharmacological target for the treatment of AD-associated symptoms.

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BACKGROUND: Obstructive sleep apnea (OSA) creates a complex substrate for atrial fibrillation (AF), which is refractory to many clinically available pharmacological interventions. We investigated atrial antiarrhythmogenic properties and ventricular electrophysiological safety of small-conductance Ca2+ -activated K+ (SK)-channel inhibition in a porcine model for obstructive respiratory events. METHODS: In spontaneously breathing pigs, obstructive respiratory events were simulated by intermittent negative upper airway pressure (INAP) applied via a pressure device connected to the intubation tube. INAP was applied for 75 s, every 10 min, three times before and three times during infusion of the SK-channel inhibitor AP14145. Atrial effective refractory periods (AERP) were acquired before (pre-INAP), during (INAP) and after (post-) INAP. AF-inducibility was determined by a S1S2 atrial pacing protocol. Ventricular arrhythmicity was evaluated by heart rate adjusted QT-interval duration (QT-paced) and electromechanical window (EMW) shortening. RESULTS: During vehicle infusion, INAP transiently shortened AERP (pre-INAP: 135 ± 10 ms vs. post-INAP 101 ± 11 ms; p = .008) and increased AF-inducibility. QT-paced prolonged during INAP (pre-INAP 270 ± 7 ms vs. INAP 275 ± 7 ms; p = .04) and EMW shortened progressively throughout INAP and post-INAP (pre-INAP 80 ± 4 ms; INAP 59 ± 6 ms, post-INAP 46 ± 10 ms). AP14145 prolonged baseline AERP, partially prevented INAP-induced AERP-shortening and reduced AF-susceptibility. AP14145 did not alter QT-paced at baseline (pre-AP14145 270 ± 7 ms vs. AP14145 268 ± 6 ms, p = .83) or QT-paced and EMW-shortening during INAP. CONCLUSION: In a pig model for obstructive respiratory events, the SK-channel-inhibitor AP14145 prevented INAP-associated AERP-shortening and AF-susceptibility without impairing ventricular electrophysiology. Whether SK-channels represent a target for OSA-related AF in humans warrants further study.

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Parkinson's disease (PD), a neurodegenerative disorder, is characterized by the loss of dopaminergic (DA) neurons. The pathogenesis of PD is associated with several factors including oxidative stress, inflammation, and mitochondrial dysfunction. Ca2+ signaling plays a vital role in neuronal signaling and altered Ca2+ homeostasis has been implicated in many neuronal diseases including PD. Recently, we reported that apamin (APM), a selective antagonist of the small-conductivity Ca2+-activated K+ (SK) channel, suppresses neuroinflammatory response. However, the mechanism(s) underlying the vulnerability of DA neurons were not fully understood. In this study, we investigated whether APM affected 1-methyl-4-phenyl pyridinium (MPP+)-mediated neurotoxicity in SH-SY5Y cells and rat embryo primary mesencephalic neurons. We found that APM decreased Ca2+ overload arising from MPP+-induced neurotoxicity response through downregulating the level of CaMKII, phosphorylation of ERK, and translocation of nuclear factor NFκB/signal transducer and activator of transcription (STAT)3. Furthermore, we showed that the correlation of MPP+-mediated Ca2+ overload and ERK/NFκB/STAT3 in the neurotoxicity responses, and dopaminergic neuronal cells loss, was verified through inhibitors. Our findings showed that APM might prevent loss of DA neurons via inhibition of Ca2+-overload-mediated signaling pathway and provide insights regarding the potential use of APM in treating neurodegenerative diseases.

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Lipopolysaccharide (LPS), an outer component of Gram-negative bacteria, induces a strong response of innate immunity via microglia, which triggers a modulation of the intrinsic excitability of neurons. However, it is unclear whether the modulation of neurophysiological properties is similar among neurons. Here, we found the hypoexcitability of layer 5 (L5) pyramidal neurons after exposure to LPS in the medial prefrontal cortex (mPFC) of juvenile rats. We recorded the firing frequency of L5 pyramidal neurons long-lastingly under in vitro whole-cell patch-clamp, and we found a reduction of the firing frequency after applying LPS. A decrease in the intrinsic excitability against LPS-exposure was also found in L2/3 pyramidal neurons but not in fast-spiking interneurons. The decrease in the excitability by immune-activation was underlain by increased activity of small-conductance Ca2+-activated K+ channels (SK channels) in the pyramidal neurons and tumor necrosis factor (TNF)-α released from microglia. We revealed that the reduction of the firing frequency of L5 pyramidal neurons was dependent on intraneuronal Ca2+ and PP2B. These results suggest the hypoexcitability of pyramidal neurons caused by the upregulation of SK channels via Ca2+-dependent phosphatase during acute inflammation in the mPFC. Such a mechanism is in contrast to that of cerebellar Purkinje cells, in which immune activation induces hyperexcitability via downregulation of SK channels. Further, a decrease in the frequency of spontaneous inhibitory synaptic transmission reflected network hypoactivity. Therefore, our results suggest that the directionality of the intrinsic plasticity by microglia is not consistent, depending on the brain region and the cell type.

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Potassium ion channels are extensively involved in the regulation of epileptic seizures. The small conductance calcium-sensitive potassium channels (SK channels) and ATP-sensitive potassium (KATP) channels are activated by calcium ion entry and decrease ATP levels, respectively. These channels can underlie the post-burst afterhyperpolarization and be upregulated during seizures, providing negative feedback during epileptic activity. Using the whole-cell patch-clamp method in rat brain slices, we investigated the effect of SK- and KATP-affecting drugs on seizure-like events (SLEs) in the 4-aminopyridine model of epileptic seizures in vitro. We demonstrate that SK and KATP channels contribute to sustaining the high-frequency firing of the principal neurons in the deep layers of the entorhinal cortex during injections of depolarizing current and epileptiform discharges. Neither the pharmacological blockade nor the activation of these channels was able to prevent the epileptiform activity in brain slices. However, the blockade of KATP channels increases the SLE duration, suggesting that these channels may contribute to the termination of SLEs. Thus, KATP channels can be considered a promising target for pharmacological interventions for the treatment of epilepsy.

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Essential tremor is one of the most prevalent movement disorders. Propranolol and primidone are the first-line pharmacological therapies. They provide symptomatic control in less than 50% of patients. Topiramate, alprazolam, clonazepam, gabapentin, and botulinum toxin injections are the next line of treatments. These medications lead to modest improvements and are therefore commonly used as add-on agents. Surgical therapies, including deep brain stimulation (DBS) surgery and focused ultrasound beam targeted to the thalamus, are considered for treating tremor refractory to medications and lead to greater than 75% improvements in tremor symptoms. However, DBS is a costly and an invasive procedure; some patients report tolerance to benefits. Focused ultrasound therapy leading to brain lesions is associated with a possibility for permanent clinical deficits. Therefore, research efforts to develop the next generation of oral medications with greater benefits and lesser adverse effects are warranted. There is considerable evidence that the increased functions of calcium channels (P/Q-type and T-type channels) and reduced functions of calcium-activated potassium channels (SK channels) located in the neuronal membranes lead to tremor oscillations. Consequently, many new pharmacological studies have targeted these channels to leverage better clinical outcomes. The current review will discuss the pathophysiology, the specific importance of these channels, and the early clinical experience of using compounds targeting these channels to treat essential tremor.

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Increased excitability and contractility of detrusor smooth muscle (DSM) cells are associated with overactive bladder (OAB), which is often induced by obesity. Small-conductance Ca2+-activated K+ (SK) channels regulate the excitability and contractility of DSM cells. Selective pharmacological activation of SK channels attenuates hyperpolarization and the decreased relaxation effect in DSM cells in obesity-induced OAB. However, additional data are needed to confirm the regulatory effect of SK channels on the function of DSM cells in obesity-related OAB. The tested hypothesis was that activation of SK channels decreases modulation of DSM function in a rat model of obesity-related OAB. Female Sprague Dawley rats were fed a normal diet (ND) or a high-fat diet (HFD), weighed after 12 weeks, and subjected to urodynamic study, patch-clamp electrophysiology, and isometric tension recording. The average body weight and incidence of OAB were increased in the HFD group. Patch-clamp studies revealed that pharmacological activation of SK channels with SKA-31 had attenuated hyperpolarization of DSM cells. In addition, isometric tension recordings indicated that SKA-31 decreased relaxation of spontaneous phasic contractions of DSM strips in the HFD group. Attenuated function of SK channels increased the excitability and contractility of DSM cells, which contributed to the occurrence of OAB, suggesting that SK channels are potential therapeutic targets for control of OAB.

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The vascular endothelium is an important regulator of vascular reactivity and preserves the balance between vasoconstrictor and vasodilator tone during normal physiologic conditions. Example endothelial-derived vasoconstrictors include endothelin-1 and thromboxane A2; example vasodilators include nitric oxide and prostacyclin. A growing body of evidence points to the existence of a non-nitric oxide, non-prostacyclin endothelium-derived vasodilatory factor of currently unclear identity, often referred to as endothelium-derived hyperpolarizing factor (EDHF). Recent research testifies to the significance of EDHF in endothelium-dependent vascular smooth muscle relaxation. Special emphasis has been placed on the role of small conductance calcium-activated potassium channels (SK) in facilitating the endothelial and vascular responses to EDHF across the microcirculation, including coronary, mesenteric, and pulmonary vascular beds. Meanwhile, decreased activity of endothelial SK channel activity has been implicated in the pathology of a variety of disease states that alter the balance between vasodilator and vasoconstrictor tone. Hence the primary goal of this review is to characterize the physiology of endothelial SK channels in the microvasculature under normal and pathological conditions. Themes of regulation and dysregulation of SK channel activity through the action of protein kinases, reactive oxygen species, and byproducts of intermediary metabolism provide unifying principles to tie together vascular pathology in altered metabolic states ranging from hypertension to diabetes, to ischemia-reperfusion. A comprehensive understanding of SK channel pathophysiology may provide a foundation for development of new therapeutics targeting SK channels, particularly SK channel potentiators, that may have widespread application for many chronic disease states.

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RATIONALE: The voltage-insensitive, small-conductance calcium-activated potassium (SK) channel is a key regulator of neuronal depolarization and is implicated in the pathophysiology of depressive disorders. OBJECTIVE: We ascertained whether the SK channel is impaired in the chronic unpredictable stress (CUS) model and whether it can serve as a molecular target of antidepressant action. METHODS: We assessed the depressive-like behavioral phenotype of CUS-exposed rats and performed post-mortem SK channel binding and activity-dependent zif268 mRNA analyses on their brains. To begin an assessment of SK channel subtypes involved, we examined the effects of genetic and pharmacological inhibition of the SK3 channel using conditional knockout mice and selective SK3 channel negative allosteric modulators (NAMs). RESULTS: We found that [125I]apamin binding to SK channels is increased in the prefrontal cortex and decreased in the hippocampus, an effect that was associated with reciprocal levels of zif268 mRNA transcripts indicating abnormal regional cell activity in this model. We found that genetic and pharmacological manipulations significantly decreased immobility in the forced swim test without altering general locomotor activity, a hallmark of antidepressant-like activity. CONCLUSIONS: Taken together, these findings link depression-related neural and behavioral pathophysiology with abnormal SK channel functioning and suggest that this can be reversed by the selective inhibition of SK3 channels.

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BACKGROUND: Atrial dilation is an important risk factor for atrial fibrillation (AF) and animal studies have found that acute atrial dilation shortens the atrial effective refractory period (AERP) and increases the risk of AF. Stretch activated ion channels (SACs) and calcium channels play a role in this. The expression profile and calcium dependent activation makes the small conductance calcium activated K+ channel (KCa2.x) a candidate for coupling stretch induced increases in intracellular calcium through K+-efflux and thereby shortening of atrial refractoriness. OBJECTIVES: We hypothesized that KCa2.x channel inhibitors can prevent the stretch induced shortening of AERP and protect the heart from AF. METHODS: The effect of KCa2 channel inhibitor (N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) 1 µM) was investigated using the isolated perfused rabbit heart preparation. To stretch the left atrium (LA) a balloon was inserted and inflated. AERP and action potential duration (APD) were recorded before and after atrial stretch. AF was induced by burst pacing the LA at different degrees of atrial stretch. RESULTS: Stretching of the LA by increasing the balloon pressure from 0 to 20 mmHg shortened the AERP by 8.6 ± 1 ms. In comparison, the KCa2 inhibitor ICA significantly attenuated the stretch induced shortening of AERP to 2.5 ± 1.1 ms. Total AF duration increased linearly with atrial balloon pressure. This relationship was not found in the presence of ICA. ICA lowered the incidence of AF induction and total AF duration. CONCLUSION: The KCa2 channel inhibitor ICA attenuates the acute stretch induced shortening of AERP and decreases stretch induced vulnerability to AF.

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Air turbulence ensures that in a natural environment insects tend to encounter odor stimuli in a pulsatile fashion. The frequency and duration of odor pulses varies with distance from the source, and hence successful mid-flight odor tracking requires resolution of spatiotemporal pulse dynamics. This requires both olfactory and mechanosensory input (from wind speed), a form of sensory integration observed within the antennal lobe (AL). In this work, we employ a model of the moth AL to study the effect of mechanosensory input on AL responses to pulsatile stimuli; in particular, we examine the ability of model neurons to: (1) encode the temporal length of a stimulus pulse; (2) resolve the temporal dynamics of a high frequency train of brief stimulus pulses. We find that AL glomeruli receiving olfactory input are adept at encoding the temporal length of a stimulus pulse but less effective at tracking the temporal dynamics of a pulse train, while glomeruli receiving mechanosensory input but little olfactory input can efficiently track the temporal dynamics of high frequency pulse delivery but poorly encode the duration of an individual pulse. Furthermore, we show that stronger intrinsic small-conductance calcium-dependent potassium (SK) currents tend to skew cells toward being better trackers of pulse frequency, while weaker SK currents tend to entail better encoding of the temporal length of individual pulses. We speculate a possible functional division of labor within the AL, wherein, for a particular odor, glomeruli receiving strong olfactory input exhibit prolonged spiking responses that facilitate detailed discrimination of odor features, while glomeruli receiving mechanosensory input (but little olfactory input) serve to resolve the temporal dynamics of brief, pulsatile odor encounters. Finally, we discuss how this hypothesis extends to explaining the functional significance of intraglomerular variability in observed phase II response patterns of AL neurons.

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Background: Secondhand smoke (SHS), a major indoor pollutant, is a significant risk factor for cardiovascular morbidity and mortality including arrhythmias and sudden cardiac death. Exposure to SHS can produce autonomic imbalance, as evidenced by reduced heart rate variability (HRV)-a clinical metric of cardiac vagal regulation. Currently, the mechanisms through which SHS changes the vagal preganglionic neuronal inputs to the heart to produce this remains unknown. Objectives: To characterize the effect of SHS on both the excitability and action potential (AP) characteristics of anatomically identified cardiac vagal neurons (CVNs) in the nucleus ambiguus and examine whether SHS alters small conductance calcium-activated potassium (SK) channel activity of these CVNs. Methods: Adult male mice were exposed to four weeks of filtered air or SHS (3 mg/m3) 6 h/day, 5 day/week. Using patch-clamp recordings on identified CVNs in brainstem slices, we determined neuronal excitability and AP characteristics with depolarizing step- and ramp-current injections. Results: Four weeks of SHS exposure reduced spiking responses to depolarizing current injections and increased AP voltage threshold in CVNs. Perfusion with apamin (20 nM) magnified these SHS-induced effects, suggesting reduced SK channel activity may serve to minimize the SHS-induced decreases in CVNs excitability. Medium afterhyperpolarization (a measurement of SK channel activity) was smaller in the SHS group, further supporting a lower SK channel activity. AP amplitude, rise rate, fast afterhyperpolarization amplitude (a measurement of voltage-gated channel activity), and decay rate were higher in the SHS group at membrane voltages more positive to 0 mV, suggesting altered inactivation properties of voltage-dependent channels underlying APs. Discussion: SHS exposure reduced neuronal excitability of CVNs with compensatory attenuation of SK channel activity and altered AP characteristics. Neuroplasticity of CVNs could blunt regulatory cardiac vagal signaling and contribute to the cardiovascular consequences associated with SHS exposure, including reduced HRV.

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AIMS: Pharmacological termination of atrial fibrillation (AF) remains a challenge due to limited efficacy and potential ventricular proarrhythmic effects of antiarrhythmic drugs. SK channels are proposed as atrial-specific targets in the treatment of AF. Here, we investigated the effects of the new SK channel inhibitor AP14145. METHODS AND RESULTS: Eight goats were implanted with pericardial electrodes for induction of AF (30 days). In an open-chest study, the atrial conduction velocity (CV) and effective refractory period (ERP) were measured during pacing. High-density mapping of both atrial free-walls was performed during AF and conduction properties were assessed. All measurements were performed at baseline and during AP14145 infusion [10 mg/kg/h (n = 1) or 20 mg/kg/h (n = 6)]. At an infusion rate of 20 mg/kg/h, AF terminated in five of six goats. AP14145 profoundly increased ERP and reduced CV during pacing. AP14145 increased spatiotemporal instability of conduction at short pacing cycle lengths. Atrial fibrillation cycle length and pathlength (AF cycle length × CV) underwent a strong dose-dependent prolongation. Conduction velocity during AF remained unchanged and conduction patterns remained complex until the last seconds before AF termination, during which a sudden and profound organization of fibrillatory conduction occurred. CONCLUSION: AP14145 provided a successful therapy for termination of persistent AF in goats. During AF, AP14145 caused an ERP and AF cycle length prolongation. AP14145 slowed CV during fast pacing but did not lead to a further decrease during AF. Termination of AF was preceded by an abrupt organization of AF with a decline in the number of fibrillation waves.

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AIM: Effective antiarrhythmic treatment of atrial fibrillation (AF) constitutes a major challenge, in particular, when concomitant heart failure (HF) is present. HF-associated atrial arrhythmogenesis is distinctly characterized by prolonged atrial refractoriness. Small-conductance, calcium-activated K+ (KCa, SK, KCNN) channels contribute to cardiac action potential repolarization and are implicated in AF susceptibility and therapy. The mechanistic impact of AF/HF-related triggers on atrial KCa channels is not known. We hypothesized that tachycardia, stretch, ß-adrenergic stimulation, and hypoxia differentially determine KCa2.1-2.3 channel remodeling in atrial cells. METHODS: KCNN1-3 transcript levels were assessed in AF/HF patients and in a pig model of atrial tachypacing-induced AF with reduced left ventricular function. HL-1 atrial myocytes were subjected to proarrhythmic triggers to investigate the effects on Kcnn mRNA and KCa channel protein. RESULTS: Atrial KCNN1-3 expression was reduced in AF/HF patients. KCNN2 and KCNN3 suppression was recapitulated in the corresponding pig model. In contrast to human AF, KCNN1 remained unchanged in pigs. Channel- and stressor-specific remodeling was revealed in vitro. Lower expression levels of KCNN1/KCa2.1 were linked to stretch and ß-adrenergic stimulation. Furthermore, KCNN3/KCa2.3 expression was suppressed upon tachypacing and hypoxia. Finally, KCNN2/KCa2.2 abundance was specifically enhanced by hypoxia. CONCLUSION: Reduction of KCa2.1-2.3 channel expression might contribute to the action potential prolongation in AF complicated by HF. Subtype-specific KCa2 channel remodeling induced by tachypacing, stretch, ß-adrenergic stimulation, or hypoxia is expected to differentially determine atrial remodeling, depending on patient-specific activation of each triggering factor. Stressor-dependent KCa2 regulation in atrial myocytes provides a starting point for mechanism-based antiarrhythmic therapy.

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The effect of brain extracellular matrix (ECM) on synaptic plasticity remains controversial. Here, we show that targeted enzymatic attenuation with chondroitinase ABC (ChABC) of ECM triggers the appearance of new glutamatergic synapses on hippocampal pyramidal neurons, thereby increasing the amplitude of field EPSPs while decreasing both the mean miniature EPSC amplitude and AMPA/NMDA ratio. Although the increased proportion of 'unpotentiated' synapses caused by ECM attenuation should promote long-term potentiation (LTP), surprisingly, LTP was suppressed. The upregulation of small conductance Ca2+-activated K+ (SK) channels decreased the excitability of pyramidal neurons, thereby suppressing LTP. A blockade of SK channels restored cell excitability and enhanced LTP; this enhancement was abolished by a blockade of Rho-associated protein kinase (ROCK), which is involved in the maturation of dendritic spines. Thus, targeting ECM elicits the appearance of new synapses, which can have potential applications in regenerative medicine. However, this process is compensated for by a reduction in postsynaptic neuron excitability, preventing network overexcitation at the expense of synaptic plasticity.

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Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the world. Although much technological progress in the treatment of AF has been made, there is an urgent need for better treatment of AF due to its high rates of morbidity and mortality. The anti-arrhythmic drugs currently approved for marketing have significant limitations and side effects such as life-threatening ventricular arrhythmias and hypotension. The small conductance Ca2+-activated K+ channels (SK channels) are dependent on intracellular Ca2+ concentrations, which tightly integrate with membrane potential. Given the predominant expression in the atria of many species, including humans, they are now emerging as a therapeutic target for treating AF. This review aimed to illustrate the characteristics and function of SK channels. Moreover, it discussed the regulation of SK channels and their potential as a therapeutic target of AF.

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Small-conductance Ca2+-activated K+ (SK, KCa2) channels are encoded by KCNN genes, including KCNN1, 2, and 3. The channels play critical roles in the regulation of cardiac excitability and are gated solely by beat-to-beat changes in intracellular Ca2+. The family of SK channels consists of three members with differential sensitivity to apamin. All three isoforms are expressed in human hearts. Studies over the past two decades have provided evidence to substantiate the pivotal roles of SK channels, not only in healthy heart but also with diseases including atrial fibrillation (AF), ventricular arrhythmia, and heart failure (HF). SK channels are prominently expressed in atrial myocytes and pacemaking cells, compared to ventricular cells. However, the channels are significantly upregulated in ventricular myocytes in HF and pulmonary veins in AF models. Interests in cardiac SK channels are further fueled by recent studies suggesting the possible roles of SK channels in human AF. Therefore, SK channel may represent a novel therapeutic target for atrial arrhythmias. Furthermore, SK channel function is significantly altered by human calmodulin (CaM) mutations, linked to life-threatening arrhythmia syndromes. The current review will summarize recent progress in our understanding of cardiac SK channels and the roles of SK channels in the heart in health and disease.

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Ion channels activated around the subthreshold membrane potential determine the likelihood of neuronal firing in response to synaptic inputs, a process described as intrinsic neuronal excitability. Long-term plasticity of chemical synaptic transmission is traditionally considered the main cellular mechanism of information storage in the brain; however, voltage- and calcium-activated channels modulating the inputs or outputs of neurons are also subjects of plastic changes and play a major role in learning and memory formation. Gamma oscillations are associated with numerous higher cognitive functions such as learning and memory, but our knowledge of their dependence on intrinsic plasticity is by far limited. Here we investigated the roles of potassium and calcium channels activated at near subthreshold membrane potentials in cholinergically induced persistent gamma oscillations measured in the CA3 area of rat hippocampal slices. Among potassium channels, which are responsible for the afterhyperpolarization in CA3 pyramidal cells, we found that blockers of SK (KCa2) and KV7.2/7.3 (KCNQ2/3), but not the BK (KCa1.1) and IK (KCa3.1) channels, increased the power of gamma oscillations. On the contrary, activators of these channels had an attenuating effect without affecting the frequency. Pharmacological blockade of the low voltage-activated T-type calcium channels (CaV3.1-3.3) reduced gamma power and increased the oscillation peak frequency. Enhancement of these channels also inhibited the peak power without altering the frequency of the oscillations. The presented data suggest that voltage- and calcium-activated ion channels involved in intrinsic excitability strongly regulate the power of hippocampal gamma oscillations. Targeting these channels could represent a valuable pharmacological strategy against cognitive impairment.

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Dequalinium is used as an antimicrobial compound for oral health and other microbial infections. Derivatives of dequalinium, the bis-quinolinium cyclophanes UCL 1684 and UCL 1848, are high affinity SK potassium channel antagonists. Here we investigated these compounds as M3 muscarinic receptor (mACHR) antagonists. We used the R-CEPIAer endoplasmic reticulum calcium reporter to functionally assay for Gq-coupled receptor signaling, and investigated the bis-quinolinium cyclophanes as antagonists of M3 mACHR activation in transfected CHO cells. Given mACHR roles in airway smooth muscle (ASM) contractility, we also tested the ability of UCL 1684 to relax ASM. We find that these compounds antagonized M3 mACHRs with an IC50 of 0.27 µM for dequalinium chloride, 1.5 µM for UCL 1684 and 1.0 µM for UCL 1848. UCL 1684 also antagonized M1 (IC50 0.12 µM) and M5 (IC50 0.52 µM) mACHR responses. UCL 1684 was determined to be a competitive antagonist at M3 receptors as it increased the EC50 for carbachol without a reduction in the maximum response. The Ki for UCL1684 determined from competition binding experiments was 909 nM. UCL 1684 reduced carbachol-evoked ASM contractions (>90%, IC50 0.43 µM), and calcium mobilization in rodent and human lung ASM cells. We conclude that dequalinium and bis-quinolinium cyclophanes antagonized M3 mACHR activation at sub- to low micromolar concentrations, with UCL 1684 acting as an ASM relaxant. Caution should be taken when using these compounds to block SK potassium channels, as inhibition of mACHRs may be a side-effect if excessive concentrations are used.