J protein chaperones as novel regulators of BKCa channels

神经通讯是由离子如钠、钙、氯和钾通过通道进出细胞的运动介导的。 离子通道是由包埋在质膜中的蛋白质复合物组成的充满水的孔。 神经元通道的数量和质量是突触传递的基础。 也就是说，关于负责监测通道的折叠成熟和降解的细胞机制仍然存在许多问题。 在这项研究计划中描述的研究将开始，以解决突触伴侣机制如何调节神经元大电导钙激活的K+通道（BKCa）的细胞表达。 最近在我的实验室的实验表明，突触前J蛋白，半胱氨酸串蛋白，（CSPa）指导热休克蛋白70伴侣机制BKCa通道，导致改变BKCa表达。 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作用，并将揭示通道调节的基本特性。 正是通过获得这一关于突触伴侣的开创性信息，将出现关于哺乳动物J蛋白伴侣系统在体内的作用和机制的共识。 用于临床干预的J蛋白（和间接通道）的操纵是这一研究路线的长期目标。 参与这些拟议研究的学员将受益于我们对分子伴侣和通道的生物学作用的不断了解，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.