Novel regulators of Slo2 potassium channels

摘要 我实验室的研究重点是确定slo2通道的生理功能如何 受其他蛋白质的调节。Slo2通道是一类存在的大电导钾通道 在哺乳动物和无脊椎动物身上。人类和老鼠各自都有两个这样的通道：Slo2.1/Slick和 而线虫只有一种，即SLO-2。这些渠道被广泛表达 在神经系统中，并在塑造神经元的放电特性方面发挥重要作用。松弛的突变 在人类中，经常会导致癫痫和智力残疾。虽然slo2的生理功能 预计通道依赖于许多其他调节蛋白、分子特性和它们的 行动机制才刚刚开始被认识到。在过去的几年里，我们发现了几个 线虫SLO-2生理功能所需的蛋白质，包括两个RNA/DNA结合 蛋白质(HRPU-2和一个类似SAFB的转录调节因子暂时命名为SLTM-1)，一个RNA编辑 调节物(ADR-1)、一个蛋白酪氨酸磷酸酶(暂定命名为PTP-5)和一个假激酶 (SCYL-1)，它们都有哺乳动物同源物。我们的结果提示HRPU-2和SLTM-1调节 SLO-2通过调控PTP-5的表达发挥作用，而ADR-1则通过调控SLO-2的功能发挥作用 通过增强SCYL-1的表达。我们已经证明SCYL-1增加SLO-2 这种调节在哺乳动物SCYL1和Slack之间是保守的。 在接下来的五年里，我们的主要目标是确定PTP-5如何调节SLO-2的功能以及是否 调节机制与人类slo2和人类PTP-5同源物保守，以确定如何 HRPU-2和SLTM-1调节PTP-5的表达，并鉴定ADR-1所需的可能蛋白质- 使用正向遗传学方法依赖SCYL-1的表达。我们设想这一结果来自于 拟议的研究不仅将提供有关蠕虫SLO-2调控的重要新知识，而且 也有可能揭示slo2通道调节的进化保守机制。

Abstract The focus of research in my lab is to determine how physiological functions of Slo2 channels are regulated by other proteins. Slo2 channels are a family of large-conductance potassium channels existing in mammals as well as invertebrates. Human and mouse each have two such channels: Slo2.1/Slick and Slo2.2/Slack, whereas the nematode C. elegans has only one, SLO-2. These channels are widely expressed in the nervous system, and play important roles in shaping neuronal firing properties. Mutations of Slack in humans often cause epilepsies and intellectual disability. Although physiological functions of Slo2 channels are expected to be dependent on many other regulatory proteins, molecular identities and their mechanisms of action are only beginning to be recognized. In the past few years, we identified several proteins required for SLO-2 physiological functions in C. elegans, including two RNA/DNA binding proteins (HRPU-2 and a SAFB-like transcription modulator tentatively named SLTM-1), one RNA editing modulator (ADR-1), one protein tyrosine phosphatase (tentatively named PTP-5), and one pseudokinase (SCYL-1), which all have mammalian homologs. Our results suggest that HRPU-2 and SLTM-1 regulate SLO-2 function through controlling the expression of PTP-5, whereas ADR-1 regulates SLO-2 function through enhancing the expression of SCYL-1. We have demonstrated that SCYL-1 increases SLO-2 activity through direct interactions, and this regulation is conserved between mammalian SCYL1 and Slack. In the next five years, our major goals are to determine how PTP-5 regulates SLO-2 function and whether the regulatory mechanism is conserved with human Slo2 and a human PTP-5 homolog, to determine how HRPU-2 and SLTM-1 regulate PTP-5 expression, and to identify putative proteins required for ADR-1- dependent SCYL-1 expression using a forward genetics approach. We envision that results from the proposed studies will not only provide important new knowledge about the regulation of worm SLO-2, but also have the potential to reveal evolutionarily conserved mechanisms of Slo2 channel regulation.