SLO-2钾通道在神经系统中功能调控的分子机理研究

Slo2 channels are high-conductance potassium channels widely expressed in the mammalian nervous system. They play important roles in controlling neuronal excitability by allowing a large outward current through the cell membrane. Recent studies have established a strong link between mutations of human Slo2 channels and epileptic disorders. The expression and physiological function of a potassium channel in vivo generally depend on a variety of regulatory proteins. With respect to Slo2 channels, however, very little is known about the regulatory proteins. The nematode C. elegans has a single mammalian Slo2 channel homologue known as SLO-2, which is also widely expressed in the nervous system and plays important roles in regulating neuronal functions. This project is to take advantage of the exceptional power of C. elegans molecular genetics to identify proteins that are important to SLO-2 function in vivo. Through a genetic screen for mutants that suppressed a lethargic phenotype caused by expressing a hyperactive SLO-2 in worms, two proteins (RSE-1 and ADR-1) were identified as novel regulators of SLO-2. RSE-1 is a homologue of human heterogeneous nuclear ribonucleoprotein U (hnRNP U) whereas ADR-1 is a homologue of human adenosine deaminases acting on RNA (ADARs). Both hnRNP U and ADARs have been implicated in neurological diseases including epilepsy but the mechanisms are unclear. This project aims to identify novel SLO-2 regulatory proteins and investigate molecular mechanisms underlying the regulation, with a view to provide important information for elucidating the physiological functions and pathological roles of human Slo2 channels.

Slo2通道是一类广泛表达于哺乳动物神经系统的高电导钾离子通道，它们通过主导神经元的外向型电流而在神经元兴奋性的控制中起重要作用。研究表明人类Slo2通道的突变和癫痫症之间有密切联系。钾通道在体内的表达和生理功能通常取决于多种调节蛋白，然而目前对于Slo2通道的调节蛋白所知甚少。本课题组前期利用遗传学筛选手段鉴定了两个调控SLO-2通道的蛋白分子RSE -1和ADR- 1，在人体中RSE -1和ADR- 1蛋白的突变能造成包括癫痫在内的多种神经系统疾病，但它们的致病机制尚不清楚。本研究拟通过突变体筛选鉴定新的SLO-2通道调节蛋白，并利用分子遗传学、免疫组化、电生理等技术来揭示RSE -1、ADR- 1以及新的调节蛋白对SLO-2通道调控的分子机制，为阐明人体Slo2通道及其调节蛋白的生理功能和病理作用提供重要理论基础。