SLO family potassium channels: function and physiology

Abstract The calcium and voltage regulated BK(or SLO1)-type K+ channel is a widely expressed ion channel impacting on regulation of excitability in a variety of both excitable and inexcitable tissues. SLO1 is encoded by the kcnma1(or slo1) gene, one of four SLO family members. The ability of SLO family channels to be regulated by specific cytosolic ions arises from a large cytosolic regulatory domain, containing specific ion binding sites, that is connected to the pore-forming part of the subunits. The ability of SLO family channels to respond to changes in the cytosolic milieu makes them uniquely adapted to play negative feedback roles following activity that leads to alterations in the cytosolic ions. The Ca-regulated BK channel is particularly fascinating, since despite being encoded by a single gene, it is expressed in a wide variety of cells in each case playing very distinct physiological roles. A central tenet of the work in this laboratory is that the functional diversity and the associated broad scope of physiological roles played by BK channels arises from associated with regulatory subunits. For BK channels, tissue-specific expression of up to four different regulatory β subunits (β1-β4) and four γ subunits can define BK function and physiology. Our understanding of the loci of expression, channel composition in particular cells, and the impact of particular regulatory subunits on function and physiology remains rudimentary. β1 and β4 subunits have been implicated in hypertension and epilepsy, respectively, and other indications suggest that BK channels may be therapeutic targets in stroke, hypertension, epilepsy, and tumor growth regulation. To address the gaps in understanding of the roles of BK channels of particular subunit composition, this lab combines methods ranging from biophysical analysis of channel properties to the use of genetic knock-out (KO) of specific regulatory subunits. This permits evaluation not only of the biophysical and functional properties of channels of different auxiliary subunit composition in native cells, but also how these channels contribute to physiological roles. Furthermore, we continue to probe questions of BK channel function pertinent to channel inactivation mechanisms and stoichiometry, guided by available structural information. Recent work on animal models developed in this lab have established important roles of γ1 and γ2 subunits in defining BK channel functions in secretory epithelial cells and inner hair cells, respectively, while β-containing BK channels influence action potential firing rates and burst behavior. Future work will further probe our existing models, e.g., the role of γ1-containing BK channels in colonic epithelium. In addition, a major focus will be the development of animal models that will allow examination of β3-containing BK currents in native cells. β3-containing BK channels remain the least understood of all BK channel subunits and we seek to remedy that deficit. This project is expected to provide new insight into the physiological roles of β3 and γ1 auxiliary subunits, and the roles of BK channels containing such subunits.