HCN pacemaker channel activation is controlled by acidic lipids downstream of diacylglycerol kinase and phospholipase A2
HCN pacemaker channel activation is controlled by acidic lipids downstream of diacylglycerol kinase and phospholipase A2
复制标题
DOI：
10.1523/jneurosci.4376-06.2007
复制
发表时间：
2007-03-14
影响因子：
5.3
通讯作者：
Tibbs, Gareth R.
中科院分区：
文献类型：
--
作者：
Fogle, Keri J.;Lyashchenko, Alex K.;Tibbs, Gareth R.
超极化激活的起搏电流（I-H）有助于可兴奋细胞的阈下特性，从而影响诸如突触整合和内在节律活动的出现和频率等行为。因此，I-H的调节有助于细胞可塑性。虽然IH激活受多种神经递质调节，包括一些通过磷脂酶C（PLC）起作用的神经递质，但已知改变I-H电压依赖性的唯一第二信使是cAMP、内部质子（H（+）（I）s）和磷脂酰肌醇-4，5-磷酸。在这里，我们表明，4 β-佛波醇-12-肉豆蔻酸酯-13-乙酸酯（4 β PMA），立体选择性C-1二酰基甘油结合位点激动剂，增强野生型和cAMP/H-I（+）-解偶联超极化激活，环核苷酸调节（HCN）通道的电压依赖性开放，但不改变植物超极化激活通道，KAT 1的门控。药理学分析表明，4 β PMA通过依次激活PKC和二酰基甘油激酶（DGK）以及上调MAPK（丝裂原活化蛋白激酶）和磷脂酶A2（PLA 2）来影响HCN门控，但其作用不依赖于磷酸肌醇激酶3（PI 3 K）和PI 4K。磷脂酸和花生四烯酸（AA）直接促进HCN门控的证明表明，这些代谢产物可能分别作为DGK和PLA 2下游的信使。4 β PMA介导的最大HCN电流抑制可能源于通道与AA的相互作用，以及由调节通道门控的相同途径触发的增强的膜恢复。这些结果表明，除了cAMP和H（+）（I）s的变构作用外，神经递质介导的I-H调节对可兴奋细胞行为的调节可能通过三种信号脂质的变化来实现。
Hyperpolarization-activated pacemaker currents (I-H) contribute to the subthreshold properties of excitable cells and thereby influence behaviors such as synaptic integration and the appearance and frequency of intrinsic rhythmic activity. Accordingly, modulation of I-H contributes to cellular plasticity. Although IH activation is regulated by a plethora of neurotransmitters, including some that act via phospholipase C ( PLC), the only second messengers known to alter I-H voltage dependence are cAMP, internal protons (H (+) (I)s), and phosphatidylinositol-4,5-phosphate. Here, we show that 4 beta-phorbol-12-myristate-13-acetate (4 beta PMA), a stereoselective C-1 diacylglycerol-binding site agonist, enhances voltage-dependent opening of wild-type and cAMP/H-I(+)-uncoupled hyperpolarization-activated, cyclic nucleotide-regulated (HCN) channels, but does not alter gating of the plant hyperpolarization-activated channel, KAT1. Pharmacological analysis indicates that 4 beta PMA exerts its effects on HCN gating via sequential activation of PKC and diacylglycerol kinase (DGK) coupled with upregulation of MAPK (mitogen-activated protein kinase) and phospholipase A2 (PLA2), but its action is independent of phosphoinositide kinase 3 (PI3K) and PI4K. Demonstration that both phosphatidic acid and arachidonic acid (AA) directly facilitate HCN gating suggests that these metabolites may serve as the messengers downstream of DGK and PLA2, respectively. 4 beta PMA-mediated suppression of the maximal HCN current likely arises from channel interaction with AA coupled with an enhanced membrane retrieval triggered by the same pathways that modulate channel gating. These results indicate that regulation of excitable cell behavior by neurotransmitter-mediated modulation of I-H may be exerted via changes in three signaling lipids in addition to the allosteric actions of cAMP and H (+) (I)s.