Pedarzani P, Storm J F
Institute of Neurophysiology, University of Oslo, Norway.
Eur J Neurosci. 1996 Oct;8(10):2098-110. doi: 10.1111/j.1460-9568.1996.tb00731.x.
Noradrenaline inhibits the Ca(2+)-activated K+ current IAHP, which underlies the slow afterhyperpolarization and spike frequency adaptation in hippocampal and neocortical neurons. The resulting increase in excitability probably contributes to the state control of the forebrain during arousal and attention. The modulation of IAHP by noradrenaline has previously been shown to be mediated by beta 1 receptors, cyclic AMP and protein kinase A, but not by alpha receptors. We have now tested the possibility that alpha receptors also contribute to IAHP modulation through interaction with beta receptors, by the use of whole-cell recordings in CA1 pyramidal cells of rat hippocampal slices. The alpha-receptor agonist 6-fluoro-noradrenaline strongly potentiated the effect of isoproterenol on IAHP. The synergistic effect of 6-fluoro-noradrenaline and isoproterenol was blocked by the beta-receptor antagonist timolol, but the receptor type mediating the effect of 6-fluoro-noradrenaline could not be unequivocally identified by using alpha-receptor antagonists. The effect of high concentrations of noradrenaline on IAHP was only partly blocked by the beta-receptor antagonist timolol, and was further reduced by blocking alpha receptors, again suggesting a contribution from alpha receptors. In contrast, the effect of low concentrations of noradrenaline seemed to be potentiated by the alpha-receptor antagonist phentolamine in 57% of the cells, suggesting concentration-dependent antagonistic interaction between alpha and beta receptors. Further tests indicated that the cross-talk between 6-fluoro-noradrenaline and isoproterenol occurs upstream from cyclic AMP production, and that protein kinase A serves as a final common path for the modulation of IAHP by noradrenaline, and by the combination of 6-fluoro-noradrenaline and isoproterenol.
去甲肾上腺素抑制钙激活钾电流IAHP，该电流是海马和新皮层神经元缓慢超极化后电位及动作电位频率适应性的基础。由此导致的兴奋性增加可能有助于在觉醒和注意力集中期间对前脑状态的控制。先前已证明，去甲肾上腺素对IAHP的调节是由β1受体、环磷酸腺苷和蛋白激酶A介导的，而非α受体。我们现在通过在大鼠海马切片的CA1锥体细胞中进行全细胞记录，测试了α受体是否也通过与β受体相互作用对IAHP调节起作用。α受体激动剂6-氟去甲肾上腺素强烈增强了异丙肾上腺素对IAHP的作用。6-氟去甲肾上腺素和异丙肾上腺素的协同作用被β受体拮抗剂噻吗洛尔阻断，但使用α受体拮抗剂无法明确鉴定介导6-氟去甲肾上腺素作用的受体类型。高浓度去甲肾上腺素对IAHP的作用仅部分被β受体拮抗剂噻吗洛尔阻断，而阻断α受体后作用进一步减弱，这再次表明α受体有一定作用。相反，在57%的细胞中，低浓度去甲肾上腺素的作用似乎被α受体拮抗剂酚妥拉明增强，这表明α和β受体之间存在浓度依赖性拮抗相互作用。进一步测试表明，6-氟去甲肾上腺素和异丙肾上腺素之间的相互作用发生在环磷酸腺苷产生的上游，并且蛋白激酶A是去甲肾上腺素以及6-氟去甲肾上腺素和异丙肾上腺素联合对IAHP调节的最终共同通路。
