PI(4,5)P2 regulates the gating of NaV1.4 channels.
PI(4,5)P2 regulates the gating of NaV1.4 channels.
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DOI：
10.1085/jgp.202213255
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发表时间：
2023-06-05
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NaV通道门控被高度调节以在可兴奋组织中产生和支持动作电位放电。在这项研究中，磷酸肌醇-磷酸酶的光遗传学激活揭示了膜上的PI（4，5）P2水平调节NaV1.4通道的生理门控行为。电压门控钠（NaV）通道在大多数可兴奋细胞中密集表达，并响应去极化而激活，导致Na+离子快速流入，从而启动动作电位。NaV通道的电压依赖性激活之后几乎立即快速失活，从而设定可兴奋组织的不应期。NaV通道的门控周期受到严格调节，扰动导致一系列病理生理状态。大多数离子通道的门控特性由膜磷脂、磷脂酰肌醇（4，5）二磷酸（PI（4，5）P2）调节。然而，尚不清楚PI（4，5）P2是否调节NaV通道的活性。在这里，我们利用光遗传学激活特定的膜相关的磷酸肌醇（PI）-磷酸酶，使PI（4，5）P2去磷酸化，同时记录NaV1.4通道电流。我们发现，去磷酸化PI（4，5）P2左移的电压依赖性门控NaV1.4更超极化的膜电位，增强了晚期电流，持续快速失活后，并加快速度通道恢复从快速失活。这些作用受到外源性diC 8 PI（4，5）P2的对抗。我们提供的证据表明，PI（4，5）P2是一个负调节器，调整门控行为的NaV1.4通道。
NaV channel gating is highly regulated to generate and support action potential firing in excitable tissues. In this study, optogenetic-activation of phosphoinositide-phosphatases reveals that PI(4,5)P2 levels at the membrane tune the physiological gating behavior of NaV1.4 channels. Voltage-gated sodium (NaV) channels are densely expressed in most excitable cells and activate in response to depolarization, causing a rapid influx of Na+ ions that initiates the action potential. The voltage-dependent activation of NaV channels is followed almost instantaneously by fast inactivation, setting the refractory period of excitable tissues. The gating cycle of NaV channels is subject to tight regulation, with perturbations leading to a range of pathophysiological states. The gating properties of most ion channels are regulated by the membrane phospholipid, phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2). However, it is not known whether PI(4,5)P2 modulates the activity of NaV channels. Here, we utilize optogenetics to activate specific, membrane-associated phosphoinositide (PI)-phosphatases that dephosphorylate PI(4,5)P2 while simultaneously recording NaV1.4 channel currents. We show that dephosphorylating PI(4,5)P2 left-shifts the voltage-dependent gating of NaV1.4 to more hyperpolarized membrane potentials, augments the late current that persists after fast inactivation, and speeds the rate at which channels recover from fast inactivation. These effects are opposed by exogenous diC8PI(4,5)P2. We provide evidence that PI(4,5)P2 is a negative regulator that tunes the gating behavior of NaV1.4 channels.
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