Calcium-and metabolic state-dependent modulation of the voltage-dependent Kv2.1 channel regulates neuronal excitability in response to ischemia
Calcium-and metabolic state-dependent modulation of the voltage-dependent Kv2.1 channel regulates neuronal excitability in response to ischemia
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DOI：
10.1523/jneurosci.3370-05.2005
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发表时间：
2005-11-30
影响因子：
5.3
通讯作者：
Trimmer, JS
中科院分区：
文献类型：
--
作者：
Misonou, H;Mohapatra, DP;Trimmer, JS
缺血性中风通常伴有神经元过度兴奋（即，癫痫发作），这加剧了脑损伤。因此，抑制中风引起的过度兴奋和相关的兴奋毒性是治疗缺血性损伤的主要焦点。ATP依赖性和Ca 2+激活的K+通道都参与了抑制缺血诱导的过度兴奋的保护机制。在这里，我们提供的证据表明，Kv2.1的定位和功能，在中枢神经元的主要体树突延迟整流电压依赖性K+通道，是由缺氧/缺血引起的代谢状态和细胞内Ca 2（+）水平的变化调节。缺氧/缺血诱导大鼠脑内Kv2.1的去磷酸化和表面Kv2.1从簇移位到均匀定位。在培养的大鼠海马神经元中，化学缺血（CI）引起Kv2.1类似的去磷酸化和移位。这些事件是可逆的，并且由细胞内储存的Ca 2（+）释放和钙调神经磷酸酶介导的Kv2.1去磷酸化介导。CI还诱导神经元延迟整流电流（I-K）的电压依赖性激活的超极化转变，导致IK增强和神经元兴奋性抑制。IK阻断剂四乙铵可逆转缺血引起的兴奋性抑制，加重缺血性神经元损伤。我们的研究结果表明，Kv2.1可以作为一种新的Ca 2+和代谢状态敏感的K+通道，并表明动态调节I-K/Kv2.1对缺氧/缺血的反应抑制神经元的兴奋性，并可以在短暂的缺血损伤中提供神经保护。
Ischemic stroke is often accompanied by neuronal hyperexcitability (i.e., seizures), which aggravates brain damage. Therefore, suppressing stroke- induced hyperexcitability and associated excitoxicity is a major focus of treatment for ischemic insults. Both ATP-dependent and Ca2+-activated K+ channels have been implicated in protective mechanisms to suppress ischemia-induced hyperexcitability. Here we provide evidence that the localization and function of Kv2.1, the major somatodendritic delayed rectifier voltage-dependent K+ channel in central neurons, is regulated by hypoxia/ ischemia-induced changes in metabolic state and intracellular Ca2(+) levels. Hypoxia/ischemia in rat brain induced a dramatic dephosphorylation of Kv2.1 and the translocation of surface Kv2.1 from clusters to a uniform localization. In cultured rat hippocampal neurons, chemical ischemia (CI) elicited a similar dephosphorylation and translocation of Kv2.1. These events were reversible and were mediated by Ca2(+) release from intracellular stores and calcineurin-mediated Kv2.1 dephosphorylation. CI also induced a hyperpolarizing shift in the voltage-dependent activation of neuronal delayed rectifier currents (I-K), leading to enhanced IK and suppressed neuronal excitability. The IK blocker tetraethylammonium reversed the ischemia-induced suppression of excitability and aggravated ischemic neuronal damage. Our results show that Kv2.1 can act as a novel Ca2(+)-and metabolic state-sensitive K+ channel and suggest that dynamic modulation of I-K/Kv2.1 in response to hypoxia/ischemia suppresses neuronal excitability and could confer neuroprotection in response to brief ischemic insults.