Surges Rainer, Brewster Amy L, Bender Roland A, Beck Heinz, Feuerstein Thomas J, Baram Tallie Z
Department of Neurology, University Clinics Freiburg, Breisacher Strasse 64, 79106 Freiburg, Germany.
Eur J Neurosci. 2006 Jul;24(1):94-104. doi: 10.1111/j.1460-9568.2006.04880.x.
The hyperpolarization-activated current (I(h)) contributes to intrinsic properties and network responses of neurons. Its biophysical properties depend on the expression profiles of the underlying hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels and the presence of cyclic AMP (cAMP) that potently and differentially modulates I(h) conducted by HCN1, HCN2 and/or HCN4. Here, we studied the properties of I(h) in hippocampal CA1 pyramidal cells, the developmental evolution of the HCN-subunit isoforms that contribute to this current, and their interplay with age-dependent free cAMP concentrations, using electrophysiological, molecular and biochemical methods. I(h) amplitude increased progressively during the first four postnatal weeks, consistent with the observed overall increased expression of HCN channels. Activation kinetics of the current accelerated during this period, consonant with the quantitative reduction of mRNA and protein expression of the slow-kinetics HCN4 isoform and increased levels of HCN1. The sensitivity of I(h) to cAMP, and the contribution of the slow component to the overall I(h), decreased with age. These are likely a result of the developmentally regulated transition of the complement of HCN channel isoforms from cAMP sensitive to relatively cAMP insensitive. Thus, although hippocampal cAMP concentrations increased over twofold during the developmental period studied, the coordinated changes in expression of three HCN channel isoforms resulted in reduced effects of this signalling molecule on neuronal h currents.
超极化激活电流（I(h)）对神经元的内在特性和网络反应有贡献。其生物物理特性取决于潜在的超极化激活的环核苷酸门控（HCN）通道的表达谱以及环磷酸腺苷（cAMP）的存在，cAMP能有效且差异性地调节由HCN1、HCN2和/或HCN4介导的I(h)。在此，我们使用电生理、分子和生化方法研究了海马CA1锥体神经元中I(h)的特性、对该电流有贡献的HCN亚基异构体的发育演变以及它们与年龄依赖性游离cAMP浓度的相互作用。出生后的前四周内，I(h)幅度逐渐增加，这与观察到的HCN通道整体表达增加一致。在此期间，电流的激活动力学加快，这与慢动力学HCN4异构体的mRNA和蛋白表达定量减少以及HCN1水平增加相一致。I(h)对cAMP的敏感性以及慢成分对整体I(h)的贡献随年龄降低。这些可能是HCN通道异构体组成从对cAMP敏感向相对不敏感发育调控转变的结果。因此，尽管在所研究的发育期间海马cAMP浓度增加了两倍多，但三种HCN通道异构体表达的协同变化导致该信号分子对神经元h电流的影响降低。
