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Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects.

Chen XQ, Zhang J, Neumeyer JL, Jin GZ, Hu GY, Zhang A, Zhen X - PLoS ONE (2009)

Bottom Line: The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity.The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel.The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel.

View Article: PubMed Central - PubMed

Affiliation: State Key laboratory of Drug Research, Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
(+/-) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotection remains elusive. We report here that (+/-) SKF83959 is a potent blocker for delayed rectifier K(+) channel. (+/-) SKF83959 inhibited the delayed rectifier K(+) current (I(K)) dose-dependently in rat hippocampal neurons. The IC(50) value for inhibition of I(K) was 41.9+/-2.3 microM (Hill coefficient = 1.81+/-0.13, n = 6), whereas that for inhibition of I(A) was 307.9+/-38.5 microM (Hill coefficient = 1.37+/-0.08, n = 6). Thus, (+/-) SKF83959 is 7.3-fold more potent in suppressing I(K) than I(A). Moreover, the inhibition of I(K) by (+/-) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel. The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel. We also tested the enantiomers of (+/-) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited I(K). However, (+/-) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of I(K) , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (+/-) SKF83959.

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Inhibition of voltage-activated K+ currents by (±) SKF83959 in rat hippocampal neurons.(A) Upper and lower are the respective representative traces of the delayed rectifier K+ current (IK) and fast transient K+ current (IA) recorded prior to and during superfusion with (±) SKF83959 (100 µM) and after 10 s of washout. The neuron was held at −50 mV. Upper inset shows the pulse protocol to elicit IK, whereas lower inset shows the protocol to elicit the total K+ current. IA is the subtraction of IK from the total K+ current. (B) and (C) Time courses of the inhibition of IK and IA by (±) SKF83959 (100 µM, n = 5 for each). The bar denotes the surpufusion with SKF83959. A number of symbols in (B) and (C) have error bars smaller than their size.
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pone-0005811-g002: Inhibition of voltage-activated K+ currents by (±) SKF83959 in rat hippocampal neurons.(A) Upper and lower are the respective representative traces of the delayed rectifier K+ current (IK) and fast transient K+ current (IA) recorded prior to and during superfusion with (±) SKF83959 (100 µM) and after 10 s of washout. The neuron was held at −50 mV. Upper inset shows the pulse protocol to elicit IK, whereas lower inset shows the protocol to elicit the total K+ current. IA is the subtraction of IK from the total K+ current. (B) and (C) Time courses of the inhibition of IK and IA by (±) SKF83959 (100 µM, n = 5 for each). The bar denotes the surpufusion with SKF83959. A number of symbols in (B) and (C) have error bars smaller than their size.

Mentions: Superfusion with (±) SKF83959 (10–1000 µM) inhibited both IK and IA in concentration-dependent manner. However, the compound preferentially inhibited IK to IA. As shown in Fig. 2A, (±) SKF83959 (100 µM) markedly suppressed IK, whereas a moderate reduction in the amplitude of IA was observed. The inhibition of (±) SKF83959 on both K+ currents had a rapid onset, as it reached steady-state levels within 10 s. Moreover, the K+ currents were partially recovered upon washing out the compound (Fig. 2B, 2C). The partial recovery may be because of the run-down of the currents with recording, or due to the incompletely drug washing- out.


Arylbenzazepines are potent modulators for the delayed rectifier K+ channel: a potential mechanism for their neuroprotective effects.

Chen XQ, Zhang J, Neumeyer JL, Jin GZ, Hu GY, Zhang A, Zhen X - PLoS ONE (2009)

Inhibition of voltage-activated K+ currents by (±) SKF83959 in rat hippocampal neurons.(A) Upper and lower are the respective representative traces of the delayed rectifier K+ current (IK) and fast transient K+ current (IA) recorded prior to and during superfusion with (±) SKF83959 (100 µM) and after 10 s of washout. The neuron was held at −50 mV. Upper inset shows the pulse protocol to elicit IK, whereas lower inset shows the protocol to elicit the total K+ current. IA is the subtraction of IK from the total K+ current. (B) and (C) Time courses of the inhibition of IK and IA by (±) SKF83959 (100 µM, n = 5 for each). The bar denotes the surpufusion with SKF83959. A number of symbols in (B) and (C) have error bars smaller than their size.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690691&req=5

pone-0005811-g002: Inhibition of voltage-activated K+ currents by (±) SKF83959 in rat hippocampal neurons.(A) Upper and lower are the respective representative traces of the delayed rectifier K+ current (IK) and fast transient K+ current (IA) recorded prior to and during superfusion with (±) SKF83959 (100 µM) and after 10 s of washout. The neuron was held at −50 mV. Upper inset shows the pulse protocol to elicit IK, whereas lower inset shows the protocol to elicit the total K+ current. IA is the subtraction of IK from the total K+ current. (B) and (C) Time courses of the inhibition of IK and IA by (±) SKF83959 (100 µM, n = 5 for each). The bar denotes the surpufusion with SKF83959. A number of symbols in (B) and (C) have error bars smaller than their size.
Mentions: Superfusion with (±) SKF83959 (10–1000 µM) inhibited both IK and IA in concentration-dependent manner. However, the compound preferentially inhibited IK to IA. As shown in Fig. 2A, (±) SKF83959 (100 µM) markedly suppressed IK, whereas a moderate reduction in the amplitude of IA was observed. The inhibition of (±) SKF83959 on both K+ currents had a rapid onset, as it reached steady-state levels within 10 s. Moreover, the K+ currents were partially recovered upon washing out the compound (Fig. 2B, 2C). The partial recovery may be because of the run-down of the currents with recording, or due to the incompletely drug washing- out.

Bottom Line: The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity.The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel.The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel.

View Article: PubMed Central - PubMed

Affiliation: State Key laboratory of Drug Research, Department of Pharmacology II, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

ABSTRACT
(+/-) SKF83959, like many other arylbenzazepines, elicits powerful neuroprotection in vitro and in vivo. The neuroprotective action of the compound was found to partially depend on its D(1)-like dopamine receptor agonistic activity. The precise mechanism for the (+/-) SKF83959-mediated neuroprotection remains elusive. We report here that (+/-) SKF83959 is a potent blocker for delayed rectifier K(+) channel. (+/-) SKF83959 inhibited the delayed rectifier K(+) current (I(K)) dose-dependently in rat hippocampal neurons. The IC(50) value for inhibition of I(K) was 41.9+/-2.3 microM (Hill coefficient = 1.81+/-0.13, n = 6), whereas that for inhibition of I(A) was 307.9+/-38.5 microM (Hill coefficient = 1.37+/-0.08, n = 6). Thus, (+/-) SKF83959 is 7.3-fold more potent in suppressing I(K) than I(A). Moreover, the inhibition of I(K) by (+/-) SKF83959 was voltage-dependent and not related to dopamine receptors. The rapidly onset of inhibition and recovery suggests that the inhibition resulted from a direct interaction of (+/-) SKF83959 with the K(+) channel. The intracellular application of (+/-) SKF83959 had no effects of on I(K), indicating that the compound most likely acts at the outer mouth of the pore of K(+) channel. We also tested the enantiomers of (+/-) SKF83959, R-(+) SKF83959 (MCL-201), and S-(-) SKF83959 (MCL-202), as well as SKF38393; all these compounds inhibited I(K). However, (+/-) SKF83959, at either 0.1 or 1 mM, exhibited the strongest inhibition on the currents among all tested drug. The present findings not only revealed a new potent blocker of I(K) , but also provided a novel mechanism for the neuroprotective action of arylbenzazepines such as (+/-) SKF83959.

Show MeSH