Zhu M, Gelband C H, Posner P, Sumners C
Department of Physiology, College of Medicine, and University of Florida Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
J Neurophysiol. 1999 Sep;82(3):1560-8. doi: 10.1152/jn.1999.82.3.1560.
Angiotensin II (Ang II) acts at specific receptors located on neurons in the hypothalamus and brain stem to elicit alterations in blood pressure, fluid intake, and hormone secretion. These actions of Ang II are mediated via Ang II type 1 (AT1) receptors and involve modulation of membrane ionic currents and neuronal activity. In previous studies we utilized neurons cultured from the hypothalamus and brain stem of newborn rats to investigate the AT1 receptor-mediated effects of Ang II on neuronal K+ currents. Our data indicate that Ang II decreases neuronal delayed rectifier (Kv) current, and that this effect is partially due to activation of protein kinase C (PKC), specifically PKCalpha. However, the data also indicated that another Ca2+-dependent mechanism was also involved in addition to PKC. Because Ca2+/calmodulin-dependent protein kinase II (CaM KII) is a known modulator of K+ currents in neurons, we investigated the role of this enzyme in the AT1 receptor-mediated reduction of neuronal Kv current by Ang II. The reduction of neuronal Kv current by Ang II was attenuated by selective inhibition of either calmodulin or CaM KII and was mimicked by intracellular application of activated (autothiophosphorylated) CaM KIIalpha. Concurrent inhibition of CaM KII and PKC completely abolished the reduction of neuronal Kv by Ang II. Consistent with these findings is the demonstration that Ang II increases CaM KII activity in neuronal cultures, as evidenced by increased levels of autophosphorylated CaM KIIalpha subunit. Last, single-cell reverse transcriptase (RT)-PCR analysis revealed the presence of AT1 receptor-, CaM KIIalpha-, and PKCalpha subunit mRNAs in neurons that responded to Ang II with a decrease in Kv current. The present data indicate that the AT1 receptor-mediated reduction of neuronal Kv current by Ang II involves a Ca2+/calmodulin/CaM KII pathway, in addition to the previously documented involvement of PKC.
血管紧张素II（Ang II）作用于位于下丘脑和脑干神经元上的特定受体，引发血压、液体摄入和激素分泌的改变。Ang II的这些作用是通过1型血管紧张素II（AT1）受体介导的，涉及膜离子电流和神经元活动的调节。在先前的研究中，我们利用新生大鼠下丘脑和脑干培养的神经元来研究Ang II对神经元钾离子电流的AT1受体介导的作用。我们的数据表明，Ang II降低神经元延迟整流钾电流（Kv），且这种作用部分归因于蛋白激酶C（PKC）的激活，特别是PKCalpha。然而，数据还表明，除了PKC外，还涉及另一种钙依赖性机制。因为钙/钙调蛋白依赖性蛋白激酶II（CaM KII）是神经元中钾离子电流的已知调节剂，我们研究了该酶在Ang II介导的AT1受体对神经元Kv电流减少中的作用。通过选择性抑制钙调蛋白或CaM KII可减弱Ang II对神经元Kv电流的减少，并且通过细胞内应用活化的（自身硫代磷酸化的）CaM KIIalpha可模拟这种减少。同时抑制CaM KII和PKC可完全消除Ang II对神经元钾电流的减少。与这些发现一致的是，Ang II增加了神经元培养物中CaM KII的活性，这可通过自身磷酸化的CaM KIIalpha亚基水平升高得到证明。最后，单细胞逆转录酶（RT）-PCR分析显示，在对Ang II反应导致Kv电流减少的神经元中存在AT1受体、CaM KIIalpha和PKCalpha亚基的mRNA。目前的数据表明，除了先前记录的PKC参与外，Ang II通过AT1受体介导的神经元Kv电流减少还涉及钙/钙调蛋白/CaM KII途径。
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