Nitric oxide activates leak K+ currents in the presumed cholinergic neuron of basal Forebrain
Nitric oxide activates leak K+ currents in the presumed cholinergic neuron of basal Forebrain
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DOI：
10.1152/jn.00536.2007
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发表时间：
2007-12-01
影响因子：
2.5
通讯作者：
Hirai, Toshihiro
中科院分区：
文献类型：
--
作者：
Kang, Youngnam;Dempo, Yoshie;Hirai, Toshihiro
学习和记忆的关键是依赖于基底前脑胆碱能（BFC）神经元的兴奋性，这是深刻的调节泄漏钾通道。许多神经调节剂关闭泄漏钾通道已被报道，而其内源性开放剂仍然未知。我们在这里证明，一氧化氮（NO）可以是内源性开放的泄漏钾通道在假定的BFC神经元。浴应用1 mM的S-亚硝基-N-乙酰青霉胺（SNAP），一个NO供体，诱导了一个持久的超极化，这往往是由短暂的去极化中断。可溶性鸟苷酸环化酶抑制剂阻止SNAP诱导超极化，但允许SNAP引起去极化，而浴应用0.2 mM 8-溴-鸟苷-3 '，5' -环单磷酸（8-Br-cGMP）单独诱导类似的持久超极化。这些观察结果表明SNAP诱导的超极化和去极化分别由cGMP依赖性和非依赖性过程介导。在电压钳条件下，施加-70 mV的斜坡脉冲，8-Br-cGMP诱导的外向电流在K+平衡电位（E-K）处发生逆转，并呈现Goldman-Hodgkin-Katz整流，表明存在电压非依赖性K+电流。相比之下，SNAP在假定的BFC神经元中的应用或者用无GTP的内溶液透析，或者在10 μ M RP-8-溴-β-苯基-1，N-2-乙烯基鸟苷3 ′，5 ′-环硫代磷酸钠盐（一种蛋白激酶G（PKG）抑制剂）存在下透析，诱导的内向电流在比E-K负得多的电位下发生反转，接近于Na+ -K+泵电流的反转电位。这些结果表明，NO通过cGMP-PKG依赖性途径激活漏钾通道，显著降低BFC神经元的兴奋性，同时通过ATP耗竭抑制Na ~+ -K ~+泵，引起去极化。
Learning and memory are critically dependent on basal forebrain cholinergic (BFC) neuron excitability, which is modulated profoundly by leak K+ channels. Many neuro-modulators closing leak K+ channels have been reported, whereas their endogenous opener remained unknown. We here demonstrate that nitric oxide (NO) can be the endogenous opener of leak K+ channels in the presumed BFC neurons. Bath application of 1 mM S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, induced a long-lasting hyperpolarization, which was often interrupted by a transient depolarization. Soluble guanylyl cyclase inhibitors prevented SNAP from inducing hyperpolarization but allowed SNAP to cause depolarization, whereas bath application of 0.2 mM 8-bromo-guanosine-3', 5' -cyclomonophosphate (8-Br-cGMP) induced a similar long-lasting hyperpolarization alone. These observations indicate that the SNAP-induced hyperpolarization and depolarization are mediated by the cGMP-dependent and -independent processes, respectively. When examined with the ramp command pulse applied at -70 mV under the voltage-clamp condition, 8-Br-cGMP application induced the outward current that reversed at K+ equilibrium potential (E-K) and displayed Goldman-Hodgkin-Katz rectification, indicating the involvement of voltage-independent K+ current. By contrast, SNAP application in the presumed BFC neurons either dialyzed with the GTP-free internal solution or in the presence of 10 mu M Rp-8-bromo-beta-phenyl-1, N-2-ethenoguanosine 3',5' -cyclic monophosphorothioate sodium salt, a protein kinase G (PKG) inhibitor, induced the inward current that reversed at potentials much more negative than E K and close to the reversal potential of Na+ -K+ pump current. These observations strongly suggest that NO activates leak K+ channels through cGMP-PKG-dependent pathway to markedly decrease the excitability in BFC neurons, while NO simultaneously causes depolarization by the inhibition of Na+ -K+ pump through ATP depletion.