Department of Pharmacology, Wayne State University School of Medicine, Detroit Michigan 48230, USA.
J Neurosci. 2010 Oct 27;30(43):14361-5. doi: 10.1523/JNEUROSCI.3440-10.2010.
Many neurons in the nervous systems express afterhyperpolarizations that are mediated by a slow calcium-activated potassium current. This current shapes neuronal firing and is inhibited by neuromodulators, suggesting an important role in the regulation of neuronal function. Surprisingly, very little is currently known about the molecular basis for this current or how it is gated by calcium. Recently, the neuronal calcium sensor protein hippocalcin was identified as a calcium sensor for the slow afterhyperpolarizing current in the hippocampus. However, while hippocalcin is very strongly expressed in the hippocampus, this protein shows a relatively restricted distribution in the brain. Furthermore, the genetic deletion of this protein only partly reduces the slow hyperpolarizing current in hippocampus. These considerations question whether hippocalcin can be the sole calcium sensor for the slow afterhyperpolarizing current. Here we use loss of function and overexpression strategies to show that hippocalcin functions as a calcium sensor for the slow afterhyperpolarizing current in the cerebral cortex, an area where hippocalcin is expressed at much lower levels than in hippocampus. In addition we show that neurocalcin δ, but not VILIP-2, can also act as a calcium sensor for the slow afterhyperpolarizing current. Finally we show that hippocalcin and neurocalcin δ both increase the calcium sensitivity of the afterhyperpolarizing current but do not alter its sensitivity to inhibition by carbachol acting through the Gαq-11-PLCβ signaling cascade. These results point to a general role for a subgroup of visinin-like neuronal calcium sensor proteins in the activation of the slow calcium-activated afterhyperpolarizing current.
神经系统中的许多神经元表达由缓慢钙激活钾电流介导的超极化后电流。该电流塑造神经元的发射，并被神经调质抑制，表明其在神经元功能调节中具有重要作用。令人惊讶的是，目前对于该电流的分子基础以及钙如何对其门控知之甚少。最近，神经元钙传感器蛋白 hippocalcin 被鉴定为海马体中缓慢超极化后电流的钙传感器。然而，虽然 hippocalcin 在海马体中表达非常强烈，但这种蛋白质在大脑中的分布相对受限。此外，该蛋白的基因缺失仅部分减少了海马体中的缓慢超极化电流。这些考虑质疑 hippocalcin 是否可以成为缓慢超极化后电流的唯一钙传感器。在这里，我们使用功能丧失和过表达策略表明 hippocalcin 作为大脑皮层缓慢超极化后电流的钙传感器发挥作用，在该区域，hippocalcin 的表达水平远低于海马体。此外，我们还表明 neurocalcin δ 而不是 VILIP-2 也可以作为缓慢超极化后电流的钙传感器。最后，我们表明 hippocalcin 和 neurocalcin δ 都增加了超极化后电流的钙敏感性，但不改变其对通过 Gαq-11-PLCβ 信号级联作用的 carbachol 的抑制敏感性。这些结果表明，一组特定的 visinin 样神经元钙传感器蛋白在缓慢钙激活的超极化后电流的激活中具有普遍作用。
