Gating in BKCaChannels

Ion channels are a class of membrane-spanning proteins that are central to many cellular processes and represent a quintessential example of structure-function relationship. They allow ions to pass in and out of the cell to enable the cell to generate electric signals and the passage is regulated by gating. Gating, ie. the stimuli-dependent opening and closing process of the ion channel, involves a transition from one structural conformation to another. Many physiological experiments can explain the function of the channel but the lack of structural data makes it difficult to relate this structural change to the function. We are therefore using an array of computational techniques to help bridge this gap.

A small motif called AC region in the cytoplasmic domain (in RCK1) has been found to be important in coupling Ca2+ binding to channel opening (see Figure above). In collaboration with Jianmin Cui’s lab (Washington University), we have shown that this region confers the majority of Ca2+ sensitivity, and chimeras of mouse and Drosophila BK channels where the AC regions have been switched following the gating behavior of the AC region (i.e. the WT mouse mslo channel looks like the Drosophila dslo channel with the mouse AC region and vice versa). Through molecular dynamics simulations, we were able to link these differences to the altered motion of αB. Further, a single point mutation of D369G in this region leads to an increase in Ca2+ sensitivity and has been directly linked to epilepsy and related disorders (hence is termed the Epilepsy and Paroxysmal Dyskinesia or EPD mutation ). Analysis of our simulations indicates that allosteric effects acting through the AC region couple the binding of Ca2+ in the DRDD loop with the movement of two alpha helices directly adjacent to the pore region. Our results and predictions match very well with parallel experimental studies and should provide new insights into the structure, dynamics, and gating function of this and other ion channels.