Targeting BK (big potassium) channels in epilepsy (original) (raw)
Related papers
Expert opinion on therapeutic targets, 2015
BK (big potassium) channels are Ca(2+)-activated K(+) channels widely expressed in mammalian cells. They are extensively distributed in the CNS, the most abundant level being found in brain areas largely involved in epilepsy, namely cortex, hippocampus, piriform cortex, and other limbic structures. BK channels control action potential shape/duration, thereby regulating membrane excitability and Ca(2+) signaling. Areas covered: The potassium channel superfamily represents a rich source of potential targets for therapeutic intervention in epilepsy. Some studies have identified alterations in BK channel function, therefore, supporting the development of drugs acting on these channels for epilepsy treatment. Expert opinion: The actual sketch is intriguing and controversial, since mechanisms altering the physiological role of BK channels leading to either a loss- or gain-of-function have both been linked to seizure onset. Not many studies have been performed to unravel the efficacy of dr...
K+ channelepsy: Progress in the neurobiology of potassium channels and epilepsy
2013
K + channels are important determinants of seizure susceptibility. These membrane proteins, encoded by more than 70 genes, make the largest group of ion channels that fine-tune the electrical activity of neuronal and non-neuronal cells in the brain. Their ubiquity and extremely high genetic and functional diversity, unmatched by any other ion channel type, place K + channels as primary targets of genetic variations or perturbations in K + -dependent homeostasis, even in the absence of a primary channel defect. It is therefore not surprising that numerous inherited or acquired K + channels dysfunctions have been associated with several neurologic syndromes, including epilepsy, which often generate confusion in the classification of the associated diseases. Therefore, we propose to name the K + channels defects underlying distinct epilepsies as "K + channelepsies," and introduce a new nomenclature (e.g., Kx.y-channelepsy), following the widely used K + channel classification, which could be also adopted to easily identify other channelopathies involving Na + (e.g., Na v x.y-phenotype), Ca 2+ (e.g., Ca v x.y-phenotype), and Cl − channels. Furthermore, we discuss novel genetic defects in K + channels and associated proteins that underlie distinct epileptic phenotypes in humans, and analyze critically the recent progress in the neurobiology of this disease that has also been provided by investigations on valuable animal models of epilepsy. The abundant and varied lines of evidence discussed here strongly foster assessments for variations in genes encoding for K + channels and associated proteins in patients with idiopathic epilepsy, provide new avenues for future investigations, and highlight these proteins as critical pharmacological targets.
Mechanism Of Increased Bk Channel Activation From A Channel Mutation That Causes Epilepsy
Biophysical Journal, 2009
Concerted depolarization and Ca 2+ rise during neuronal action potentials activate large-conductance Ca 2+ -and voltage-dependent K + (BK) channels, whose robust K + currents increase the rate of action potential repolarization. Gain-of-function BK channels in mouse knockout of the inhibitory  4 subunit and in a human mutation ( ␣ D434G ) have been linked to epilepsy. Here, we investigate mechanisms underlying the gain-of-function effects of the equivalent mouse mutation ( ␣ D369G ), its modulation by the  4 subunit, and potential consequences of the mutation on BK currents during action potentials. Kinetic analysis in the context of the Horrigan-Aldrich allosteric gating model revealed that changes in intrinsic and Ca 2+ -dependent gating largely account for the gain-of-function effects. D369G causes a greater than twofold increase in the closed-to-open equilibrium constant (6.6e Ϫ 7 → 1.65e Ϫ 6 ) and an approximate twofold decrease in Ca 2+ -dissociation constants (closed channel: 11.3 → 5.2 μ M; open channel: 0.92 → 0.54 μ M). The  4 subunit inhibits mutant channels through a slowing of activation kinetics. In physiological recording solutions, we established the Ca 2+ dependence of current recruitment during action potential -shaped stimuli. D369G and  4 have opposing effects on BK current recruitment, where D369G reduces and  4 increases K 1/2 (K 1/2 M: ␣ WT 13.7, ␣ D369G 6.3, ␣ WT /  4 24.8, and ␣ D369G /  4 15.0). Collectively, our results suggest that the D369G enhancement of intrinsic gating and Ca 2+ binding underlies greater contributions of BK current in the sharpening of action potentials for both ␣ and ␣ /  4 channels.
BK Ca channel dysfunction in neurological diseases
Frontiers in Physiology, 2014
The large conductance, Ca 2+-activated K + channels (BK Ca , K Ca1.1) are expressed in various brain neurons where they play important roles in regulating action potential duration, firing frequency and neurotransmitter release. Membrane potential depolarization and rising levels of intracellular Ca 2+ gated BK Ca channels, which in turn results in an outward K + flux that re/hyperpolarizes the membrane. The sensitivity of BK channels to Ca 2 Ca + provides an important negative-feedback system for Ca 2+ entry into brain neurons and suppresses repetitive firing. Thus, BK Ca channel loss-of-function gives rise to neuronal hyperexcitability, which can lead to seizures. Evidence also indicates that BK Ca channels can facilitate high-frequency firing (gain-of-function) in some brain neurons. Interestingly, both gain-of-function and loss-of-function mutations of genes encoding for various BK Ca channel subunits have been associated with the development of neuronal excitability disorders, such as seizure disorders. The role of BK Ca channels in the etiology of some neurological diseases raises the possibility that these channels can be used as molecular targets to prevent and suppress disease phenotypes.
Neuropharmacology, 2020
Small conductance calcium-activated potassium (SK) channels dampen neuronal excitability by contributing to slow afterhyperpolarization (AHP) that follows a series of action potentials, and therefore may represent an intrinsic inhibitory mechanism to prevent seizures. We have previously reported that susceptibility to acoustically evoked seizures was associated with downregulation of SK1 and SK3 subtypes of SK channels in the inferior colliculus of the moderated seizure severity strain of the genetically epilepsy-prone rats (GEPR-3s). Here, we evaluated the effects of 1ethyl-2-benzimidazolinone (1-EBIO), a potent activator of SK channels, on acoustically evoked seizures in both male and female adult GEPR-3s at various time points post-treatment. Systemic administration of 1-EBIO at various tested doses suppressed seizure susceptibility in both male and female GEPR-3s; however, the complete seizure suppression was only observed following administration of relatively higher doses of 1-EBIO in females. These findings indicate that activation of SK channels results in anticonvulsive action against generalized tonic-clonic seizures in both male and female GEPR-3s, with males exhibiting higher sensitivity than females.
International Journal of Molecular Sciences
BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary β and γ subunits to regulate Ca2+ sensitivity, voltage dependence and gating properties. BK channels are abundantly expressed throughout the brain and in different compartments within a single neuron, including axons, synaptic terminals, dendritic arbors, and spines. Their activation produces a massive efflux of K+ ions that hyperpolarizes the cellular membrane. Together with their ability to detect changes in intracellular Ca2+ concentration, BK channels control neuronal excitability and synaptic communication through diverse mechanisms. Moreover, increasing evidence indicates that dysfunction of BK channel-mediated effects on neuronal excitability and synaptic function has been implicated in several neurological disorders, including epilepsy, fragile X syndrome, mental retardation, and autism, as well as in motor and cognitive behavior. Here, we dis...
Brain Research, 2010
Small conductance calcium (Ca 2+ ) activated SK channels are critical regulators of neuronal excitability in hippocampus. Accordingly, these channels are thought to play a key role in controlling neuronal activity in acute models of epilepsy. In this study, we investigate the expression and function of SK channels in the pilocarpine model of mesial temporal lobe epilepsy. For this purpose, protein expression was assessed using western blotting assays and gene expression was analyzed using TaqMan-based probes and the quantitative real-time polymerase chain reaction (qPCR) comparative method delta-delta cycle threshold (ΔΔCT) in samples extracted from control and epileptic rats. In addition, the effect of SK channel antagonist UCL1684 and agonist NS309 on CA1 evoked population spikes was studied in hippocampal slices. Western blotting analysis showed a significant reduction in the expression of SK1 and SK2 channels at 10 days following status epilepticus (SE), but levels recovered at 1 month and at more than 2 months after SE. In contrast, a significant down-regulation of SK3 channels was detected after 10 days of SE. Analysis of gene expression by qPCR revealed a significant reduction of transcripts for SK2 (Kcnn1) and SK3 (Kcnn3) channels as early as 10 days following pilocarpineinduced SE and during the chronic phase of the pilocarpine model. Moreover, bath application of UCL1684 (100 nM for 15 min) induced a significant increase of the population spike amplitude and number of spikes in the hippocampal CA1 area of slices obtained control and chronic epileptic rats. This effect was obliterated by co-administration of UCL1684 with SK channel agonist NS309 (1 μM). Application of NS309 failed to modify population spikes in the CA1 area of slices taken from control and epileptic rats. These data indicate an abnormal expression of SK channels and a possible dysfunction of these channels in experimental MTLE.
Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy
Brain Research, 2008
In the hippocampus, BK channels are preferentially localized in presynaptic glutamatergic terminals including mossy fibers where they are thought to play an important role regulating excessive glutamate release during hyperactive states. Large conductance calcium-activated potassium channels (BK, MaxiK, Slo) have recently been implicated in the pathogenesis of genetic epilepsy. However, the role of BK channels in acquired mesial temporal lobe epilepsy (MTLE) remains unknown. Here we used immunohistochemistry, laser scanning confocal microscopy (LSCM), western immunoblotting and RT-PCR to investigate the expression pattern of the alpha-pore forming subunit of BK channels in the hippocampus and cortex of chronically epileptic rats obtained by the pilocarpine model of MTLE. All epileptic rats experiencing recurrent spontaneous seizures exhibited a significant down-regulation of BK channel immunostaining in the mossy fibers at the hilus and stratum lucidum of the CA3 area. Quantitative analysis of immunofluorescence signals by LSCM revealed a significant 47% reduction in BK channel in epileptic rats when compared to age-matched non-epileptic control rats. These data correlate with a similar reduction in BK channel protein levels and transcripts in the cortex and hippocampus. Our data indicate a seizure-related down-regulation of BK channels in chronically epileptic rats. Further functional assays are necessary to determine whether altered BK channel expression is an acquired channelopathy or a compensatory mechanism affecting the network excitability in MTLE. Moreover, seizure-mediated BK down-regulation may disturb neuronal excitability and presynaptic control at glutamatergic terminals triggering exaggerated glutamate release and seizures.
eLife
Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons. We find that patient iPSC-derived neurons exhibit faster action potential repolarization, larger post-burst afterhyperpolarization and a functional enhancement of Ca2+-activated K+ channels. These properties, which can be recapitulated by chronic inhibition of M-current in control neurons, facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. O...