Endocytosis as a mode to regulate functional expression of two-pore domain potassium (K(2P)) channels

Two-pore domain potassium (K(2P)) channels are implicated in an array of physiological and pathophysiological roles. As a result of their biophysical properties, these channels produce a background leak K(+) current which has a direct effect on cellular membrane potential and activity. The regulation of potassium leak from cells through K(2P) channels is of critical importance to cell function, development and survival. Controlling the cell surface expression of these channels is one mode to regulate their function and is achieved through a balance between regulated channel delivery to and retrieval from the cell surface. Here, we explore the modes of retrieval of K(2P) channels from the plasma membrane and observe that K(2P) channels are endocytosed in both a clathrin-mediated and clathrin-independent manner. K(2P) channels use a variety of pathways and show altered internalisation and sorting in response to external cues. These pathways working in concert, equip the cell with a range of approaches to maintain steady state levels of channels and to respond rapidly should changes in channel density be required.