From Pan-Reactive KV7 Channel Opener to Subtype Selective Opener/Inhibitor by Addition of a Methyl Group
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Abstract:
The voltage-gated potassium channels of the KV7 family (KV7.1–5) play important roles in controlling neuronal excitability and are therefore attractive targets for treatment of CNS disorders linked to hyperexcitability. One of the main challenges in developing KV7 channel active drugs has been to identify compounds capable of discriminating between the neuronally expressed subtypes (KV7.2–5), aiding the identification of the subunit composition of KV7 currents in various tissues, and possessing better therapeutic potential for particular indications. By taking advantage of the structure-activity relationship of acrylamide KV7 channel openers and the effects of these compounds on mutant KV7 channels, we have designed and synthesized a novel KV7 channel modulator with a unique profile. The compound, named SMB-1, is an inhibitor of KV7.2 and an activator of KV7.4. SMB-1 inhibits KV7.2 by reducing the current amplitude and increasing the time constant for the slow component of the activation kinetics. The activation of KV7.4 is seen as an increase in the current amplitude and a slowing of the deactivation kinetics. Experiments studying mutant channels with a compromised binding site for the KV7.2–5 opener retigabine indicate that SMB-1 binds within the same pocket as retigabine for both inhibition of KV7.2 and activation of KV7.4. SMB-1 may serve as a valuable tool for KV7 channel research and may be used as a template for further design of better subtype selective KV7 channel modulators. A compound with this profile could hold novel therapeutic potential such as the treatment of both positive and cognitive symptoms in schizophrenia.Keywords:
Voltage-gated potassium channel
Potassium channel blocker
Effect of potassium channel antagonist on proliferation in the human mammary epithelial cells MCF10A
Previous work has shown that voltage-gated potassium channels are crucial for breast cancer (e.g MCF7) cell proliferation; but the function and mechanism of these channels in proliferation of normal human mammary epithelial cells has been left largely unknown in MCF10A,so,we carry on with the study. Firstly, the effect of tetraethylammonium (TEA, a potassium channel blocker) and 4-aminopyridine (4-AP, a voltage-gated potassium channel blocker) on MCF10A cell line was detected by MTT methods. Secondly, expressions of different Kv channels, including Kv1.2, Kv1.5, were determined by blot technique. Results show that: (1)5-10mmol/L of TEA and 4-AP treatment for 72 h could significantly inhibit proliferation of MCF10A and MCF7 breast cancer cell lines; and the latter was more sensitive to both blockers. (2)Kv1.2, Kv1.5 expressed in both cell lines. The Kv1.5 protein level in MCF10A was higher than that in the MCF7 cells. These results strongly suggest that voltage-gated potassium channel-Kv1.5 may play an important physiological role in the regulation of proliferation.
Voltage-gated potassium channel
Tetraethylammonium
Potassium channel blocker
MTT assay
Channel blocker
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Functional regulation of potassium currents in developing neurons is pivotal for changes in excitability and action potential waveform. Here, we test whether an excess of potassium channel transcripts is sufficient to drive functional expression of potassium current and shortening of the duration of the action potential. Injection of Shaker-like potassium channel transcripts into two-cell stage embryos achieves increases in RNA levels. The elevated levels of potassium channel RNA produce larger delayed-rectifier currents. Action potential durations are briefer, indicating that larger potassium currents are not compensated by changes in inward currents. Strikingly, overexpression of potassium current RNA leads to a reduction in the number of morphologically differentiated neurons in culture. We suggest that, by prematurely reducing the duration of the impulse, early overexpression of potassium channel activity suppresses normal developmental cues.
Potassium channel blocker
Shaker
Voltage-gated potassium channel
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Shaker
Potassium channel blocker
Voltage-gated potassium channel
Unconsciousness
Homomeric
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A variety of voltage-sensitive potassium channels has been described which differ in their electrophysiological and pharmacological properties. Potassium channels which mediate outward K+ currents in response to changes in membrane polarisation differ most notably in their voltage sensitivity and their opening and closing kinetics, as well as their recovery times from inactivation. Also, some of these potassium channels are sensitive to toxins like dendrotoxin and mast cell degranulating peptide; others are not. We have cloned and sequenced a variety of cDNAs encoding potassium channel subunits present in invertebrate as well as vertebrate central nervous systems. Injection into Xenopus oocytes of RNA synthesized in vitro using the various cDNAs as a template results in the expression of functional potassium channels. Some of these channels exhibit properties similar to those of the non-inactivating delayed rectifier channel found in many excitable cells, yet differ in their sensitivities towards potassium channel blocking agents. The properties of other channels expressed from cRNA injected into Xenopus oocytes resemble those of transient A-type channels which inactivate rapidly after opening upon membrane depolarisation. A comparison of the derived primary sequences of the different potassium channels allows a direct correlation of channel protein structures with electrophysiological and pharmacological properties, respectively.
Voltage-gated potassium channel
Potassium channel blocker
Calcium-activated potassium channel
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Voltage-gated potassium channel
Potassium channel blocker
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Carbon nanoparticles (CNPs) have been reported to boost plant growth, while the mechanism that CNPs enhanced potassium uptake for plant growth has not been reported so far.In this study, the function that CNPs promoted potassium uptake in BY-2 cells was established and the potassium accumulated in cells had a significant correlation with the fresh biomass of BY-2 cells. The K+ accumulation in cells increased with the increasing concentration of CNPs. The K+ influx reached high level after treatment with CNPs and was significantly higher than that of the control group and the negative group treated with K+ channels blocker, tetraethylammonium chloride (TEA+). The K+ accumulation was not reduced in the presence of CNPs inhibitors. In the presence of potassium channel blocker TEA+ or CNPs inhibitors, the NKT1 gene expression was changed compared with the control group. The CNPs were found to preferentially transport K+ than other cations determined by rectification of ion current assay (RIC) in a conical nanocapillary.These results indicated that CNPs upregulated potassium gene expression to enhance K+ accumulation in BY-2 cells. Moreover, it was speculated that the CNPs simulated protein of ion channels via bulk of carboxyl for K+ permeating. These findings will provide support for improving plant growth by carbon nanoparticles.
Tetraethylammonium
Voltage-gated potassium channel
Potassium channel blocker
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KcsA potassium channel
Tetraethylammonium
Potassium channel blocker
Voltage-gated potassium channel
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Background:Dalfampridine (4-aminopyridine; 4-AP) is a potassium channel blocker that has been available in the United States as a treatment to improve walking in patients with multiple sclerosis. 4-AP is well-characterized in vitro with regard to inhibition of neuronal potassium channels, but the potential contribution of its metabolites to clinical activity has not been determined. This study evaluated the concentration–response of 4-AP and its two primary metabolites, 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate, for inhibition of the potassium channels Kv 1.1, Kv 1.2, and Kv 1.4, which are considered candidates for mediating effects of 4-AP on action potential conduction because of their presence in axonal membranes.Methods:Stable transfection of cDNA for Kv 1.1, Kv 1.2, and Kv 1.4 was performed into HEK293 cells, and colonies of cells containing each channel were selected and maintained under appropriate cell culture conditions. Electrophysiological measurements were performed using a patch-clamp technique in at least three cells for each concentration (50, 500, 5000, and 50,000 μM) of 4-AP and the two metabolites, with each cell acting as its own control. Concentration–response curves were constructed for 4-AP and each metabolite. Data were analyzed using nonlinear least-squares fit, and concentrations inhibiting the channels by 50% (IC50) were estimated.Results:4-AP induced similar concentration-dependent inhibition profiles of all three potassium channels, resulting in a narrow range of IC50 values across channels (242 µM to 399 µM). Across the three channels, the IC50 values of 3-hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate were 1–2 orders of magnitude higher (less potent) than those of 4-AP.Conclusions:3-Hydroxy-4-aminopyridine and 3-hydroxy-4-aminopyridine sulfate demonstrated low in vitro potency for Kv 1.1, Kv 1.2, and Kv 1.4 inhibition, suggesting that these metabolites are unlikely to contribute to the positive pharmacodynamic effects of 4-AP. A limitation of this study is that while the metabolites were substantially less active at these representative potassium channels in vitro, the untested possibility exists that they may be active at one or more of the many other channel types that occur in vivo.
4-Aminopyridine
Potassium channel blocker
IC50
Voltage-gated potassium channel
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Voltage-gated potassium channel
R-type calcium channel
KcsA potassium channel
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To explored the expression of potassium channels and the effects of potassium channel blockers on the proliferation in human osterosarcoma cells,the expressions of potassium channels,including kv1.1,kv1.3,kv1.5,kv2.1,kv3.3/3.4,kv4.1,kv5.1,kv9.3,herg,heag and kcnq1,were measured by RT-PCR in three human osteosarcoma cell lines of MG63,Saos-2 and SOSP-9607. Nonspecific kv channel blocker ( 4-AP and CSCl) and specific HERG,HEAG and KCa channel blocker (E-4031,imipramine and TEA respectively ) were used to examine the functional role of potassium channels in the proliferation regulation by means of MTT. The mRNA transcripts of kv1.3,kv1.5,kv2.1,kv3.3/3.4,kv4.1,kv9.3,herg and heag are detected in all three osterosarcom cell lines,kv5.1 in MG63 and kcnq1 in SOSP-9607 and MG63 cells by RT-PCR. E-4031,imipramine and TEA had no significant effects on the proliferation. But 4-AP,at 3mmol and 5mmol,significantly suppressed the cell proliferation. CSCl at 5mmol also had a similar effects to 4-AP but minor. These results demonstrated that potassium channels are broadly expressed in the three human ostersarcoma cells at transcript level. But only kv potassium channels involved in the proliferation regulation.
hERG
Voltage-gated potassium channel
Potassium channel blocker
MTT assay
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