Modulation of TTX-sensitive voltage-dependent Na+ channels by β-bungarotoxin in rat cerebellar neurons.
Modulation of TTX-sensitive voltage-dependent Na+ channels by β-bungarotoxin in rat cerebellar neurons.
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DOI：
10.1186/1471-2202-13-36
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发表时间：
2012-03-29
期刊：
影响因子：
2.4
通讯作者：
Strauss O
中科院分区：
文献类型：
--
作者：
Guo D;Xiang W;Seebahn A;Becker CM;Strauss O
脂质代谢物如花生四烯酸或类花生酸对电压依赖性Na+通道的调节在生理功能以及退行性疾病中起作用。迄今为止，TTX抗性通道主要受脂质代谢产物的调节。我们使用具有内在磷脂酶A2活性的β-银环蛇毒素（β-BuTX，10 pM）和阻断原代小脑神经元中环氧合酶活性的吲哚美辛（10 μM）研究了TTX-s Na+通道的脂质依赖性调节。为了研究TTX-s Na+通道，在无K+条件下测量全电流，并用10 nM TTX阻断。通过计算在存在和不存在TTX的情况下测量的电流的差异得到的电流用于进一步分析。吲哚美辛的应用主要改变了电流动力学，但对电压依赖性的影响很小。相反，β-BuTX使最大电流幅值增加，并使电压依赖性激活向更负的电位移动。β-BuTX的作用可被吲哚美辛阻断。使用MALDI-TOF MS分析通过β-BuTX处理积累的脂质代谢物，显示与花生四烯酸相关的环氧合酶反应产物增加。总之，我们得出结论，TTX敏感的Na+通道可以直接调制环氧合酶反应产物导致更高的活性，在较低的去极化电位和随后的神经元的兴奋性较高。由于环氧合酶的活化也参与导致凋亡细胞死亡的途径，这可能在CNS的退行性疾病中起作用，并突出了环氧合酶抑制的可能保护作用。
The modulation of voltage-dependent Na+ channels by lipid metabolites such as arachidonic acid or eicosanoids plays a role in physiological functions as well as in degenerative diseases. So far TTX-resistant channels were found mainly to be regulated by lipid metabolites. We investigated the lipid-dependent modulation of TTX-sensitive (TTX-s) Na+ channels using β-bungarotoxin (β-BuTX, 10 pM), which has an intrinsic phospholipase-A2 activity, and indomethacin (10 μM), which blocks cyclooxygenase activity in primary cerebellar neurons. To investigate TTX-s Na+ channels, whole-currents were measured under K+-free conditions and blocked by 10 nM TTX. The currents resulting from calculating the difference of currents measured in the presence and the absence of TTX were used for further analysis. Application of indomethacin mainly changed the current kinetics but has only minor effects on voltage-dependence. In contrast β-BuTX increased the maximal current amplitude and shifted the voltage-dependent activation towards more negative potentials. The effects of β-BuTX were blocked by indomethacin. Analysis of lipid metabolites which accumulate by treatment with β-BuTX using MALDI-TOF MS showed an increase of cyclooxygenase reaction products in relation to arachidonic acid. In summary, we conclude that TTX-sensitive Na+ channels can be directly modulated by cyclooxygenase reaction products leading to higher activity at less depolarized potentials and subsequent higher excitability of neurons. Since activation of cyclooxygenase is also involved in pathways leading to apoptotic cells death this could play a role in degenerative diseases of the CNS and highlights a possible protective effect of cyclooxygenase inhibition.
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影响因子：
2
作者：
Kadoi, Jun;Takeda, M.;Matsumoto, S.
通讯作者：
Matsumoto, S.
影响因子：
5.5
作者：
ELLIOTT, AA;ELLIOTT, JR
通讯作者：
ELLIOTT, JR
影响因子：
1.7
作者：
Kerr, BJ;Souslova, V;Wood, JN
通讯作者：
Wood, JN
DOI：
10.1152/ajpcell.1997.272.2.c592
发表时间：
1997-02-01
影响因子：
5.5
作者：
Bendahhou, S;Cummins, TR;Agnew, WS
通讯作者：
Agnew, WS
影响因子：
3.4
作者：
Herkert, M;Shakhman, O;Becker, CM
通讯作者：
Becker, CM