J protein chaperones as novel regulators of BKCa channels

神经通讯是由钠、钙、氯和钾等离子通过通道进出细胞而调节的。离子通道是由嵌入在质膜中的蛋白质复合体组成的充满水的孔。神经元通道的数量和质量是突触传递的基础。尽管如此，关于负责监测通道折叠成熟和降解的细胞机制仍然存在许多问题。这项研究计划中描述的研究将开始讨论突触伴侣机制如何调节神经元大电导钙激活K+通道(BKCa)的细胞表达。我的实验室最近的实验表明，突触前J蛋白，半胱氨酸串蛋白(CSPA)将Hsp70伴侣机制导向BKCa通道，导致BKCa表达改变。从我们的研究中获得的信息将确定细胞伴侣在K+通道功能调节中的新角色，并将揭示通道调节的基本特性。正是通过获得这一突触伴侣的开创性信息，将对哺乳动物J蛋白伴侣系统在体内的作用(S)和机制(S)达成共识。操纵J蛋白(和间接通道)用于临床干预是这项研究的长期目标。参加这些拟议研究的受训者将受益于我们对分子伴侣和通道的生物学作用的不断增长的了解，以及发展强大的神经细胞生物学技能。

Neural communication is mediated by the movement of ions such as sodium, calcium, chloride and potassium into and out of cells via channels. Ion channels are water filled pores composed of protein complexes embedded in the plasma membrane. The quantity and quality of neuronal channels is fundamental to synaptic transmission. That said, many questions remain regarding the cellular machinery responsible for monitoring folding maturation and degradation of channels. The studies described in this research proposal will begin to address how the synaptic chaperone machinery regulates the cellular expression of the neuronal large conductance calcium-activated K+ channels (BKCa). Recent experiments in my laboratory have revealed that the presynaptic J protein, cysteine string protein, (CSPa) directs the Hsp70 chaperone machinery to BKCa channels, leading to altered BKCa expression. The information gained from our research will identify novel roles of cellular chaperones in the regulation of K+ channel function and will uncover fundamental properities of channel regulation. It is through the acquisition of this pioneering information about synaptic chaperones that a consensus will emerge as to the role(s) and mechanisms(s) of mammalian J protein chaperone systems in vivo. The manipulation of J proteins (and indirectly channels) for clinical intervention is a long term goal of this line of investigation. Trainees participating in these proposed studies will benefit by contributing to our increasing knowledge of the biologcal role of molecular chaperones and channels as well as developing a strong neural cell biology skill set.