BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures

Brenner, Robert; Chen, Qing H.; Vilaythong, Alex; Toney, Glenn M.; Noebels, Jeffrey L.; Aldrich, Richard W.

doi:10.1038/nn1573

Cited by 324 publications

(449 citation statements)

References 46 publications

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“…Therefore, the role of BK channel dysfunction will probably be different in generalized epilepsy with thalamo-cortical involvement. Interestingly, β4-knockout mice with associated gain-of-function of BK channels in granule cells were reported to exhibit distinctive temporal lobe seizures emanating from hippocampus (Brenner et al, 2005). In this study β4 deficit enhanced the activity of BK channels that, in turn, altered the intrinsic properties of granule cells by sharpening the action potential and sustaining higher firing rates.…”

Section: Discussionmentioning

confidence: 60%

“…Supporting this notion, gene-targeted β4 (Kcnmb4) null mice display an epileptic phenotype (i.e. temporal lobe seizures) due to a gain-of-function for the BK channels (Brenner et al, 2005). Moreover, β4 deficient mice showed little spike frequency adaptation leading to a substantial increase in firing frequency.…”

Section: Introductionmentioning

confidence: 99%

“…The dentate gyrus acts as a low-pass filtering gate that limits high-frequency inputs into the hippocampus (Heinemann et al, 1992;Nadler, 2003). Hence, β4 modulation on intrinsic firing properties of granule cells may protect against epileptogenesis (Brenner et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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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: 60%

Section: Introductionmentioning

confidence: 99%

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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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“…Our data indicate that the resulting increase in protons might enhance the activity of two very different types of channels that would have opposing effects on membrane voltage. The wide and varied expression patterns of ASIC channels (1-4) and BK and related K ϩ channels (22,23,(38)(39)(40)(41)(42)(43) suggest that they might interact in a variety of cell types and brain regions. In addition, finding that more than one ASIC can inhibit BK, that ASIC1a can inhibit more than one type of K ϩ channel, and that BK influences ASIC1a current suggests many intriguing opportunities to alter cell signaling, neuronal sensory function, and membrane excitability.…”

Section: Discussionmentioning

confidence: 99%

Acid-sensing ion channels interact with and inhibit BK K ⁺ channels

Petroff

Price²,

Snitsarev³

et al. 2008

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

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Acid-sensing ion channels (ASICs) are neuronal non-voltage-gated cation channels that are activated when extracellular pH falls. They contribute to sensory function and nociception in the peripheral nervous system, and in the brain they contribute to synaptic plasticity and fear responses. Some of the physiologic consequences of disrupting ASIC genes in mice suggested that ASIC channels might modulate neuronal function by mechanisms in addition to their H ؉ -evoked opening. Within ASIC channel's large extracellular domain, we identified sequence resembling that in scorpion toxins that inhibit K ؉ channels. Therefore, we tested the hypothesis that ASIC channels might inhibit K ؉ channel function by coexpressing ASIC1a and the high-conductance Ca 2؉ -and voltageactivated K ؉ (BK) channel. We found that ASIC1a associated with BK channels and inhibited their current. Reducing extracellular pH disrupted the association and relieved the inhibition. BK channels, in turn, altered the kinetics of ASIC1a current. In addition to BK, ASIC1a inhibited voltage-gated Kv1.3 channels. Other ASIC channels also inhibited BK, although acidosis-dependent relief of inhibition varied. These results reveal a mechanism of ion channel interaction and reciprocal regulation. Finding that a reduced pH activated ASIC1a and relieved BK inhibition suggests that extracellular protons may enhance the activity of channels with opposing effects on membrane voltage. The wide and varied expression patterns of ASICs, BK, and related K ؉ channels suggest broad opportunities for this signaling system to alter neuronal function.

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“…KCNMA1 ͉ acylation ͉ protein kinase A ͉ maxi-K L arge conductance calcium-and voltage-gated potassium (BK) channels are potently regulated by protein phosphorylation (1) and are important determinants of neuronal, cardiovascular, endocrine, and epithelial function where channel dysfunction may lead to major disorders such as hypertension (2,3), ataxia (4), epilepsy (5,6), and incontinence (7). BK channels are potently regulated by phosphorylation, and several putative phosphorylation motifs on the pore-forming ␣-subunit have been identified (8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Palmitoylation gates phosphorylation-dependent regulation of BK potassium channels

Tian

Jeffries

McClafferty

et al. 2008

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

105

180

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Large conductance calcium-and voltage-gated potassium (BK) channels are important regulators of physiological homeostasis and their function is potently modulated by protein kinase A (PKA) phosphorylation. PKA regulates the channel through phosphorylation of residues within the intracellular C terminus of the poreforming ␣-subunits. However, the molecular mechanism(s) by which phosphorylation of the ␣-subunit effects changes in channel activity are unknown. Inhibition of BK channels by PKA depends on phosphorylation of only a single ␣-subunit in the channel tetramer containing an alternatively spliced insert (STREX) suggesting that phosphorylation results in major conformational rearrangements of the C terminus. Here, we define the mechanism of PKA inhibition of BK channels and demonstrate that this regulation is conditional on the palmitoylation status of the channel. We show that the cytosolic C terminus of the STREX BK channel uniquely interacts with the plasma membrane via palmitoylation of evolutionarily conserved cysteine residues in the STREX insert. PKA phosphorylation of the serine residue immediately upstream of the conserved palmitoylated cysteine residues within STREX dissociates the C terminus from the plasma membrane, inhibiting STREX channel activity. Abolition of STREX palmitoylation by site-directed mutagenesis or pharmacological inhibition of palmitoyl transferases prevents PKA-mediated inhibition of BK channels. Thus, palmitoylation gates BK channel regulation by PKA phosphorylation. Palmitoylation and phosphorylation are both dynamically regulated; thus, cross-talk between these 2 major posttranslational signaling cascades provides a mechanism for conditional regulation of BK channels. Interplay of these distinct signaling cascades has important implications for the dynamic regulation of BK channels and physiological homeostasis.L arge conductance calcium-and voltage-gated potassium (BK) channels are potently regulated by protein phosphorylation (1) and are important determinants of neuronal, cardiovascular, endocrine, and epithelial function where channel dysfunction may lead to major disorders such as hypertension (2, 3), ataxia (4), epilepsy (5, 6), and incontinence (7). BK channels are potently regulated by phosphorylation, and several putative phosphorylation motifs on the pore-forming ␣-subunit have been identified (8-12). However, as for other potassium channels, the molecular basis through which phosphorylation of the ␣-subunit effects changes in BK channel activity is essentially unknown.BK channel pore-forming ␣-subunits are encoded by a single gene, KCNMA1 (13), and native BK channels show functional heterogeneity in their response to protein kinase A (PKA)-mediated phosphorylation. This diversity results, in large part, from the extensive alternative pre-mRNA splicing of the pore-forming ␣-subunits (10, 12). Previous studies have demonstrated that PKA phosphorylation of a conserved C-terminal phosphorylation motif. RQPS 899 results in BK channel activation (9,10,14). Inclusion of ...

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BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures

Cited by 324 publications

References 46 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

Acid-sensing ion channels interact with and inhibit BK K ⁺ channels

Palmitoylation gates phosphorylation-dependent regulation of BK potassium channels

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BK channel β4 subunit reduces dentate gyrus excitability and protects against temporal lobe seizures

Cited by 324 publications

References 46 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

Acid-sensing ion channels interact with and inhibit BK K + channels

Palmitoylation gates phosphorylation-dependent regulation of BK potassium channels

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Acid-sensing ion channels interact with and inhibit BK K ⁺ channels