Is there a Therapeutic Future for ‘Potassium Channel Openers’?

Lawson, Kim

doi:10.1042/cs0910651

Cited by 18 publications

(7 citation statements)

References 80 publications

(72 reference statements)

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“…Thus, rat hippocampal BK channels not only regulate somatic excitability, but are also specifically targeted to the active zone of presynaptic glutamatergic terminals where they can limit glutamate release under conditions of increased Ca 2+ influx [17]. BK channels may therefore provide a neuroprotective ‘emergency brake’ when there is excessive depolarization and [Ca 2+ ] i accumulation, such as during cerebral ischemia [11], [17], [18], [49]. We have now for the first time tested this hypothesis directly by selective suppression of BK channel activity, using BK −/− mice [27].…”

Section: Discussionmentioning

confidence: 99%

Neuronal Ca2+-Activated K+ Channels Limit Brain Infarction and Promote Survival

et al. 2010

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Neuronal calcium-activated potassium channels of the BK type are activated by membrane depolarization and intracellular Ca2+ ions. It has been suggested that these channels may play a key neuroprotective role during and after brain ischemia, but this hypothesis has so far not been tested by selective BK-channel manipulations in vivo. To elucidate the in vivo contribution of neuronal BK channels in acute focal cerebral ischemia, we performed middle cerebral artery occlusion (MCAO) in mice lacking BK channels (homozygous mice lacking the BK channel alpha subunit, BK−/−). MCAO was performed in BK−/− and WT mice for 90 minutes followed by a 7-hour-reperfusion period. Coronal 1 mm thick sections were stained with 2,3,5-triphenyltetrazolium chloride to reveal the infarction area. We found that transient focal cerebral ischemia by MCAO produced larger infarct volume, more severe neurological deficits, and higher post-ischemic mortality in BK−/− mice compared to WT littermates. However, the regional cerebral blood flow was not significantly different between genotypes as measured by Laser Doppler (LD) flowmetry pre-ischemically, intra-ischemically, and post-ischemically, suggesting that the different impact of MCAO in BK−/− vs. WT was not due to vascular BK channels. Furthermore, when NMDA was injected intracerebrally in non-ischemic mice, NMDA-induced neurotoxicity was found to be larger in BK−/− mice compared to WT. Whole-cell patch clamp recordings from CA1 pyramidal cells in organotypic hippocampal slice cultures revealed that BK channels contribute to rapid action potential repolarization, as previously found in acute slices. When these cultures were exposed to ischemia-like conditions this induced significantly more neuronal death in BK−/− than in WT cultures. These results indicate that neuronal BK channels are important for protection against ischemic brain damage.

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Section: Discussionmentioning

confidence: 99%

Neuronal Ca2+-Activated K+ Channels Limit Brain Infarction and Promote Survival

et al. 2010

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“…Grover et al [15]. This graph refers to a paper of Lawson,4 where also the corresponding references can be found. The graph only lists main applicabilities.…”

Section: Therapeutic Profile 2asthma 21 Myocardial Ischemiamentioning

confidence: 98%

“…KCOs add to existent pharmacotherapy with potential in promoting cellular protection under conditions of metabolic stress. Preclinical evidence indicates a broad therapeutic potential for KCOs [4][5][6][7] e.g. in hypertension, cardiac ischemia, asthma, or urinary incontinence; for an overview see Fig. (1).…”

Section: Introductionmentioning

confidence: 99%

Second-Generation KATP Channel Openers

Mannhold¹,

Leclerc²

2005

MRMC

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“…Although more than 80 conotoxins have been characterized, only 2 of them, -conotoxin PVIIA and A-conotoxin SIVA, target potassium channels (17,21). Both toxins inhibit voltagegated potassium channels.…”

Section: Discussionmentioning

confidence: 99%

A Novel Conotoxin from Conus betulinus, κ-BtX, Unique in Cysteine Pattern and in Function as a Specific BK Channel Modulator

Fan

Chen

Zhang

et al. 2003

Journal of Biological Chemistry

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A novel conotoxin, -conotoxin (-BtX), has been purified and characterized from the venom of a wormhunting cone snail, Conus betulinus. The toxin, with four disulfide bonds, shares no sequence homology with any other conotoxins. Based on a partial amino acid sequence, its cDNA was cloned and sequenced. The deduced sequence consists of a 26-residue putative signal peptide, a 31-residue mature toxin, and a 13-residue extra peptide at the C terminus. The extra peptide is cleaved off by proteinase post-processing. All three Glu residues are ␥-carboxylated, one of the two Pro residues is hydroxylated at position 27, and its C-terminal residue is Pro-amidated. The monoisotopic mass of the toxin is 3569.0 Da. Electrophysiological experiments show that: 1) among voltage-gated channels, -BtX is a specific modulator of K ؉ channels; 2) among the K channels, -BtX specifically up-modulates the Ca 2؉ -and voltage-sensitive BK channels (252 ؎ 47%); 3) its EC 50 is 0.7 nM with a single binding site (Hill ‫؍‬ 0.88); 4) the time constant of wash-out is 8.3 s; and 5) -BtX has no effect on single channel conductance, but increases the open probability of BK channels. It is concluded that -BtX is a novel specific biotoxin against BK channels.

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Is there a Therapeutic Future for ‘Potassium Channel Openers’?

Cited by 18 publications

References 80 publications

Neuronal Ca2+-Activated K+ Channels Limit Brain Infarction and Promote Survival

Neuronal Ca2+-Activated K+ Channels Limit Brain Infarction and Promote Survival

Second-Generation KATP Channel Openers

A Novel Conotoxin from Conus betulinus, κ-BtX, Unique in Cysteine Pattern and in Function as a Specific BK Channel Modulator

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