Distinct domains of LINGO1 control surface expression and biophysical properties of large conductance Ca- and voltage-activated potassium (BK) channels.

Large conductance Ca and voltage-activated K (BK) channels are ubiquitous ion channels that regulate a wide array of physiological process. Their functional diversity can be modulated by accessory proteins including a family of leucine-rich repeat and immunoglobulin-like domain-containing protein (LINGO) subunits that may control both the biophysical properties and surface trafficking of BK channels. By exploiting differences in the regulation of BK channels by LINGO1 and LINGO2 subunits we have taken a chimeric approach to dissect the role of distinct domains of these single transmembrane pass proteins. We demonstrate that the large extracellular domain of LINGO1, but not the transmembrane or intracellular C-terminal tail domain (ITD), is required to inhibit plasmalemmal expression of BK channels. Importantly, this inhibitory effect did not require the 12 leucine-rich repeats) in the extracellular domain. In contrast, the ITD is important for controlling the shift in voltage of half maximal activation of BK:LINGO currents seen between LINGO1 and LINGO2 at different Ca concentrations. This effect on voltage of half maximal activation is independent of the contribution of the last 8 amino acids of the ITD, which confer inactivation on BK:LINGO currents. These data reveal that distinct domains of LINGO proteins are critical determinants of the function and properties of BK channels.