The aim of this work is to understand the functional and structural properties of an inactivation form of a large-conductance calcium (Ca2+)- and voltage-activated potassium (K+) channel (termed BK channel). BK channels play a critical role in coupling changes in submembrane Ca2+ concentrations to changes in membrane potential and excitability. BK currents among different cells exhibit markedly different apparent Ca2+ sensitivities and much of the functional diversity remains to be explained. In contrast to most previously described BK channels, most BK channels in rat chromaffin cells exhibit rapid inactivation (BKi). BKi channels are also found in the pancreas and hippocampus. The mechanism of inactivation appears to differ from mechanisms proposed for other voltage-gated channels. Using methods of electrophysiology combined with molecular biology and biochemistry, this project will define a likely inactivation mechanism and attempt to define the composition of BKi channels. First, the possible locations of barriers to ion permeation that occur during inactivation will be determined. Second, the extent to which inactivation is coupled to conformational changes associated with channel opening will be determined. Third, possible key structural components of BKi channels will be examined. Finally, the distribution and function of BKi channels in other tissues will be determined. This project will provide new information about a mechanistically unique form of channel inactivation. Furthermore, new information will be gained about possible structural changes associated with BK gating. In different tissues, BK channels contribute to regulation of neuronal excitability, smooth muscle relaxation, and hormone secretion. The BK channel is therefore of potential medical importance, not only because it may serve as an important therapeutic target but also altered function of this channel may contribute to pathological conditions.
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