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Sackler School of Graduate Biomedical Sciences

The Dan Cox Lab

Molecular Mechanisms of BKCa Channel Function

The calcium-activated potassium channel (BKCa) is an important regulator of neurotransmission and smooth-muscle contraction, and it is of vital importance to the maintenance of overall health. Studies in my lab are directed toward understanding the regulation of this channel by four essential regulators: Ca2+ ions, membrane potential, auxiliary channel subunits, and voltage-gated Ca2+ channels. Our goal is to gaining a quantitative and mechanistic understanding of the influence these regulators have on BKCa-channel activity in neurons and vascular smooth muscle. Such an understanding may have far-reaching medical implications, as it may lead to the discovery of new strategies for the treatment of stroke, epilepsy, high blood pressure, and asthma.

We use electrophysiological and molecular biological techniques, as well as mathematical modeling, to address questions having to do with the BKCa channel.  These approaches coupled with the analysis of mutants allows us to understand channel function (Figure 1). Note that the mutants analyzed in the two bottom panels D898A and D900A, eliminate the effect of an increase in Ca2+ on the channels conductance-voltage relation.

Cox Fig 1

Figure 1. BKCa Currents. The left panel shows K+ currents recorder under voltage clamp from BKCachannels expressed in Xenopus oocytes and exposed to 10 µM intracellular Ca2+. Currents from the normal channel and four mutants are displayed (A-E). The right panel shows conductance-voltage relations for these channels recorded with ~ 0, 1 and 10 µM Ca2+ exposed to the internal surface of the channels.  For more information see Bao, et al 2002.

Data like these shown above, have helped us construct a model of the “Ca2+ bowl” Ca2+ binding site of the BKCa channel (Figure 2).

Cox Fig 2

Figure 2. Model of the BKCa channels’s “Ca2+ bowl”  Ca2+ binding site. For more information, see Bao, et al 2004.