Relationship between large conductance calcium-activated potassium channel and bursting activity

Jin, Wen; Sugaya, Akira; Terada, Tadashi; Ohguchi, Hiromi; Sugaya, Eiichi

doi:10.1016/s0006-8993(00)01943-0

Cited by 76 publications

(65 citation statements)

References 25 publications

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“…For example, iberiotoxin (IbTX) completely inhibited bursting activity induced by pentylenetetrazol (PTZ), caffeine, 1,4,5-inositol triphosphate (IP3) and direct forced increase of intracellular calcium (REF). In this study, spontaneous bursting activity in the cerebral cortical neurons of the El mouse, which shows a high susceptibility to convulsions, was also completely inhibited by IbTX (Jin et al, 2000). However, insulin and leptin that inhibit epileptiform-like bursting activities in rat hippocampal neurons might involve in activation of BK channels (O'Malley et al, 2003;Shanley et al, 2002).…”

Section: Discussionmentioning

confidence: 55%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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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.

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Section: Discussionmentioning

confidence: 55%

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Otalora¹,

Hernandez²,

Arshadmansab³

et al. 2008

Brain Research

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“…Although previous studies have shown that BK antagonists can produce the paradoxical decreased excitability expected from an excitatory impact of BK currents (6,9,10,20,21), BK activation in its native context has not been previously associated with both inhibitory and excitatory influences in the same neuronal type and recording conditions. Here we show that Tg-BK R207Q firing was altered in SCN neurons, increasing at night and decreasing during the day.…”

Section: Discussionmentioning

confidence: 95%

“…BK antagonists can reduce heart rate (18), exert anticonvulsant effects (19), and decrease firing or plateau potentials (6,9,10,(20)(21)(22). Furthermore, two gain-of-function alterations, loss of the β4 subunit which slows activation and a familial mutation in Kcnma1, are linked to hyperexcitation and epilepsy (23,24).…”

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confidence: 99%

Genetic activation of BK currents in vivo generates bidirectional effects on neuronal excitability

Montgomery

Meredith

2012

Proc. Natl. Acad. Sci. U.S.A.

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Large-conductance calcium-activated potassium channels (BK) are potent negative regulators of excitability in neurons and muscle, and increasing BK current is a novel therapeutic strategy for neuroand cardioprotection, disorders of smooth muscle hyperactivity, and several psychiatric diseases. However, in some neurons, enhanced BK current is linked with seizures and paradoxical increases in excitability, potentially complicating the clinical use of agonists. The mechanisms that switch BK influence from inhibitory to excitatory are not well defined. Here we investigate this dichotomy using a gain-of-function subunit (BK R207Q ) to enhance BK currents. Heterologous expression of BK R207Q generated currents that activated at physiologically relevant voltages in lower intracellular Ca 2+ , activated faster, and deactivated slower than wild-type currents. We then used BK R207Q expression to broadly augment endogenous BK currents in vivo, generating a transgenic mouse from a circadian clock-controlled Period1 gene fragment (Tg-BK R207Q ). The specific impact on excitability was assessed in neurons of the suprachiasmatic nucleus (SCN) in the hypothalamus, a cell type where BK currents regulate spontaneous firing under distinct day and night conditions that are defined by different complements of ionic currents. In the SCN, Tg-BK R207Q expression converted the endogenous BK current to fast-activating, while maintaining similar current-voltage properties between day and night. Alteration of BK currents in Tg-BK R207Q SCN neurons increased firing at night but decreased firing during the day, demonstrating that BK currents generate bidirectional effects on neuronal firing under distinct conditions.V oltage-gated K + channels generally oppose excitability by producing hyperpolarizing current in response to membrane depolarization (1). One distinctive member of this family is the BK channel (K Ca 1.1), encoded by the Kcnma1 gene (2, 3). BK channels are widely expressed in excitable and nonexcitable cells (4), suggesting that they are highly versatile players in membrane signaling. In neurons and muscle, BK currents are activated by simultaneous membrane depolarization and an increase in intracellular Ca 2+ (Ca 2+ i ) (1, 5), shaping the falling phase of the action potential, the afterhyperpolarization (AHP), and some Ca 2+ transients that underlie neurotransmitter release and secretion (6-9). Deletion of Kcnma1 leads to a constellation of defects related to hyperexcitability (2, 10). For this reason, BK agonists have been pursued as novel targets for treating stroke, seizure, cardiac ischemia, urinary incontinence, asthma, erectile dysfunction, and hypertension (11,12). Linkage analysis and expression profiling have also implicated Kcnma1 in schizophrenia, autism, mental retardation, and alcoholism (13-17).Whereas selectively activating BK currents that suppress excitability would be therapeutically useful, a paradoxical excitatory role for BK has also been uncovered in several tissues. BK antagonists can reduce heart rate (...

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“…There are several possible mechanisms for the extinction-induced increase in bursting. Neuronal excitability can be enhanced by closing large-conductance Ca 2 -activated K potassium channels (Shao et al, 1999;Traub et al, 2003;Brenner et al, 2005) or A-type potassium channels (Perez et al, 2006;Takeda et al, 2006;Wang and Schreurs, 2006), both of which are expressed in cortical neurons (Jin et al, 2000;Dong and White, 2003) and have been linked to increased bursting (Magee and Carruth, 1999;Jin et al, 2000;Traub et al, 2003;Gu et al, 2007). Interestingly, a decrease in A-type currents has been correlated with invertebrate learning (Yamoah et al, 2005) and hippocampal long-term potentiation (Frick et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Fear Conditioning and Extinction Differentially Modify the Intrinsic Excitability of Infralimbic Neurons

Santini

Quirk²,

Porter³

2008

J. Neurosci.

242

265

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Extinction of conditioned fear is an active learning process involving inhibition of fear expression. It has been proposed that fear extinction potentiates neurons in the infralimbic (IL) prefrontal cortex, but the cellular mechanisms underlying this potentiation remain unknown. It is also not known whether this potentiation occurs locally in IL neurons as opposed to IL afferents. To determine whether extinction enhances the intrinsic excitability of IL pyramidal neurons in layers II/III and V, we performed whole-cell patch-clamp recordings in slices from naive, conditioned, or conditioned-extinguished rats. We observed that conditioning depressed IL excitability compared with slices from naive animals, as evidenced by a decreased number of spikes evoked by injected current and an increase in the slow afterhyperpolarizing potential (sAHP). Extinction reversed these conditioning-induced effects. Furthermore, IL neurons from extinguished rats showed increased burst spiking compared with naive rats, which was correlated with extinction recall. These changes were specific to IL prefrontal cortex and were not observed in prelimbic prefrontal cortex. Together, these findings suggest that IL intrinsic excitability is reduced to allow for expression of conditioning memory and enhanced for expression of extinction memory through the modulation of Ca 2ϩ -gated K ϩ channels underlying the sAHP. Inappropriate modulation of these intrinsic mechanisms may underlie anxiety disorders, characterized by exaggerated fear and deficient extinction.

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Relationship between large conductance calcium-activated potassium channel and bursting activity

Cited by 76 publications

References 25 publications

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Down-regulation of BK channel expression in the pilocarpine model of temporal lobe epilepsy

Genetic activation of BK currents in vivo generates bidirectional effects on neuronal excitability

Fear Conditioning and Extinction Differentially Modify the Intrinsic Excitability of Infralimbic Neurons

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