Dopamine modulates inwardly rectifying potassium currents in medial prefrontal cortex pyramidal neurons
Dopamine modulates inwardly rectifying potassium currents in medial prefrontal cortex pyramidal neurons
复制标题
DOI：
10.1523/jneurosci.4715-03.2004
复制
发表时间：
2004-03-24
影响因子：
5.3
通讯作者：
White, FJ
中科院分区：
文献类型：
--
作者：
Dong, Y;Cooper, D;White, FJ
多巴胺（DA）对内侧前额叶皮层（mPFC）锥体神经元兴奋性的调节引起了人们的广泛关注，因为mPFC DA参与了一些神经元疾病。在这里，我们专注于DA调制内向整流钾电流（IRKC）在锥体神经元急性分离大鼠mPFC。Cs+-敏感的全细胞IRKC是通过从-50 mV的保持电位开始的超极化电压阶跃引起的。DA（20 μ M）降低IRKC振幅，选择性刺激DA D-1或D-2类受体（D1 Rs和D（2）Rs）也是如此。D（1）Rs激活腺苷酸环化酶- cAMP -蛋白激酶A（PKA）信号通路，而D2 Rs抑制该通路.通过D2 R刺激抑制IRKC可归因于PKA活性降低，因为PKA抑制剂观察到类似的抑制，而增强PKA活性增加IRKC。这表明IRKC的DA D1 R抑制通过PKA磷酸化非依赖性过程发生。使用由外向外补丁的mPFC锥体神经元，这排除了胞质信号分子的参与，我们观察到一个Cs+敏感的宏观IRKC，被抑制的膜渗透性环核苷酸Sp-cAMP，但不受PKA的非核苷酸调节剂，表明直接相互作用的环核苷酸与IRK通道。我们的研究结果表明，DA抑制IRKC通过两种机制：D1 R激活cAMP和直接相互作用的核苷酸与IRK通道和D2 R介导的去磷酸化的IRK通道。IRKC的DA调制表明，周围的DA往往会增加对兴奋性输入的反应时，PFC神经元接近静息膜电位，并可能提供一种机制，DA影响更高的认知功能。
Dopamine (DA) modulation of excitability in medial prefrontal cortex (mPFC) pyramidal neurons has attracted considerable attention because of the involvement of mPFC DA in several neuronal disorders. Here, we focused on DA modulation of inwardly rectifying K+ current (IRKC) in pyramidal neurons acutely dissociated from rat mPFC. A Cs+-sensitive whole-cell IRKC was elicited by hyperpolarizing voltage steps from a holding potential of -50 mV. DA (20 muM) reduced IRKC amplitude, as did selective stimulation of DA D-1 or D-2 class receptors (D1Rs and D(2)Rs). D(1)Rs activate, whereas D2Rs inhibit, the adenylyl cyclase - cAMP - protein kinase A (PKA) signaling pathway. Suppression of IRKC by D2R stimulation was attributable to decreased PKA activity because similar inhibition was observed with PKA inhibitors, whereas enhancing PKA activity increased IRKC. This suggests that the DA D1R suppression of IRKC occurred through a PKA phosphorylation-independent process. Using outside-out patches of mPFC pyramidal neurons, which preclude involvement of cytosolic signaling molecules, we observed a Cs+-sensitive macroscopic IRKC that was suppressed by the membrane-permeable cyclic nucleotide Sp-cAMP but was unaffected by non-nucleotide modulators of PKA, suggesting direct interactions of the cyclic nucleotides with IRK channels. Our results indicate that DA suppresses IRKC through two mechanisms: D1R activation of cAMP and direct interactions of the nucleotide with IRK channels and D2R-mediated dephosphorylation of IRK channels. The DA modulation of IRKC indicates that ambient DA would tend to increase responsiveness to excitatory inputs when PFC neurons are near the resting membrane potential and may provide a mechanism by which DA impacts higher cognitive function.