Large-conductance, calcium-activated potassium channels: Structural and functional implications

Ghatta, Srinivas; Nimmagadda, Deepthi; Xu, Xiaoping; O’Rourke, Stephen T.

doi:10.1016/j.pharmthera.2005.10.007

Cited by 298 publications

(289 citation statements)

References 156 publications

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“…Most data reporting the specificity of these molecules have been generated in functional studies where a dependency on BK activation in the NS-8-or NS1619-induced effects is abolished by BK-selective toxins (Holland et al, 1996;Malysz et al, 2004;Soder and Petkov, 2011). Although NS-8 is a known activator of BK (Parihar et al, 2003b;Malysz et al, 2004), NS1619 is considered to be the only selective BK opener by some authors (Ghatta et al, 2006) without any effect on KATP, voltage-gated K + , Na + or Ca 2+ channels (Olesen et al, 1994). According to previous results (Parihar et al, 2003b;Malysz et al, 2004), there are no qualitative differences between the effects induced by NS1619 and NS-8 in our experimental…”

Section: Figurementioning

confidence: 99%

Ca²⁺‐activated K⁺ channel (K_Ca) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

González‐Corrochano

Fuente

Cuevas

et al. 2013

British J Pharmacology

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Background and PurposeWe have evaluated the influence of calcium‐activated potassium channels (KCa) activation on cGMP‐mediated relaxation in human penile tissues from non‐diabetic and diabetic patients, and on the effects of PDE5 inhibitors on erectile responses in control and diabetic rats.Experimental ApproachCavernosal tissues were collected from organ donors and from patients with erectile dysfunction (ED). Relaxations of corpus cavernosum strips (HCC) and penile resistance arteries (HPRA) obtained from these specimens were evaluated. Intracavernosal pressure (ICP) increases to cavernosal nerve electrical stimulation were determined in anaesthetized diabetic and non‐diabetic rats.Key ResultsConcentration‐dependent vasodilation to the PDE5 inhibitor, sildenafil, in HPRA was sensitive to endothelium removal, NO/cGMP pathway inhibition and KCa blockade. Accordingly, activation of KCa with NS‐8 (10 μM) significantly potentiated sildenafil‐induced relaxations in HPRA (EC50 0.49 ± 0.22 vs. 5.21 ± 0.63 μM). In HCC, sildenafil‐induced relaxation was unaffected by KCa blockade or activation. Potentiating effects in HPRA were reproduced with an alternative PDE5 inhibitor (tadalafil) and KCa activator (NS1619) and prevented by removing the endothelium. Large‐conductance KCa (BK) and intermediate‐conductance KCa (IK) contribute to NS‐8‐induced effects and were immunodetected in human and rat penile arteries. NS‐8 potentiated sildenafil‐induced enhancement of erectile responses in rats. Activation of KCa recovered the impaired relaxation to sildenafil in diabetic HPRA while sildenafil completely reversed diabetes‐induced ED in rats only when combined with KCa activation.Conclusions and ImplicationsActivation of KCa improves vasodilatory capacity of PDE5 inhibitors in diabetic and non‐diabetic HPRA, resulting in the recovery of erectile function in diabetic rats. These results suggest a therapeutic potential for KCa activation in diabetic ED.

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Section: Figurementioning

confidence: 99%

Ca²⁺‐activated K⁺ channel (K_Ca) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

González‐Corrochano

Fuente

Cuevas

et al. 2013

British J Pharmacology

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“…Whereas the general functional role of BK channels is understood (Ghatta et al, 2006), their specific role for retinal signal processing is still not completely clear. Interestingly, there is much more evidence for BK channel function in the rod pathway than for the cone pathway: for instance, BK channels are expressed in amphibian rod photoreceptors and support reliable single-photon detection (Pelucchi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

BK Channels Mediate Pathway-Specific Modulation of Visual Signals in theIn VivoMouse Retina

Tanimoto¹,

Sothilingam²,

Euler³

et al. 2012

J. Neurosci.

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The modulatory role of large-conductance Ca 2ϩ -activated K ϩ (BK) channels in the nervous system has been extensively studied. In the retina, it has been shown that BK channels play a pivotal role in modulating feedback from A17 amacrine cells to rod bipolar cells (RBCs). Here, we used electroretinography to examine the functional role of BK channels for rod and cone vision in the retina in vivo using a genetically engineered mouse lacking functional BK channels (Bk). Under dark-adapted and light-adapted conditions, the lack of BK channels had no effect on photoreceptor activity, suggesting that these ion channels do not modulate photoreceptor responses.

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“…β1 to β4) that influence channel expression and biophysical properties (Lu et al, 2006;Wu, 2003). BK channel opening yields an unusually large single-channel conductance of 200-400 pS (Ghatta et al, 2006;Salkoff et al, 2006). Accordingly, the activity of a few BK channels can produce a large outward potassium current exerting a robust modulatory action on excitability.…”

Section: Introductionmentioning

confidence: 99%

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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Large-conductance, calcium-activated potassium channels: Structural and functional implications

Cited by 298 publications

References 156 publications

Ca²⁺‐activated K⁺ channel (K_Ca) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

Ca²⁺‐activated K⁺ channel (K_Ca) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

BK Channels Mediate Pathway-Specific Modulation of Visual Signals in theIn VivoMouse Retina

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

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Large-conductance, calcium-activated potassium channels: Structural and functional implications

Cited by 298 publications

References 156 publications

Ca2+‐activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

Ca2+‐activated K+ channel (KCa) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

BK Channels Mediate Pathway-Specific Modulation of Visual Signals in theIn VivoMouse Retina

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

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Ca²⁺‐activated K⁺ channel (K_Ca) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction

Ca²⁺‐activated K⁺ channel (K_Ca) stimulation improves relaxant capacity of PDE5 inhibitors in human penile arteries and recovers the reduced efficacy of PDE5 inhibition in diabetic erectile dysfunction