J protein chaperones as novel regulators of BKCa channels

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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.