research-general.gif

The Lingle lab is interested in the functional properties and physiological roles of a specific K+ ion channel, termed the BK channel, that is regulated both by membrane voltage and intracellular Ca2+ signals. This dual regulation by two distinct signals has made BK channels of interest in two important areas: first, the mechanistic question of how multiple signaling factors can converge to influence the activity of a membrane protein and, second, what the physiological roles may be of this widely expressed K+ channel. A number of genetic diseases, including hypertension and forms of epilepsy, are attributed to mutations of BK channel subunits. In addition, compounds acting on BK channels are of interest for roles as anticonvulsants, neuroprotectants (during ischemia) or as anti-hypertensive agents. Understanding BK channel function is central to understanding its roles in normal and pathological situations.

We utilize a combination of electrophysiological, biochemical, molecular, and genetic methods. To understand the functional properties of BK channels, we express BK channel subunits in heterologous systems, where the properties of the channels can be clearly studied under defined conditions. By introduction of specific mutations combined with electrical recordings of currents flowing through these channel proteins, we aim to tease apart the mechanisms of regulation of this channel and develop an understanding of its functional machinery. To understand the physiological roles of BK channels, we study BK channels in native tissue slices or isolated cells obtained either from wild-type mice and from mice in which specific BK channel subunits are genetically deleted.