O'Kelly BB/J008168/1 Cell surface expression of acid sensitive K2P channels

All cells maintain different concentrations of ions (e.g. sodium, potassium, chloride) across their cell membrane and results in a difference in charge (called the resting membrane potential; RMP) between inside and outside the cell. This membrane potential is of critical important to every cells function. Excitable cells (e.g. heart (or cardiac), brain (or neuronal) or muscle cells) could not function without a RMP. The RMP is maintained by controlling the movement of ions between the inside and outside of the cell. Ions need to travel through specialised channels called ion channels to move from one side of the cell membrane to the other. This proposal focuses on an ion channel that is key to maintaining the RMP of cells, these channels are called two-pore domain potassium (K2P) channels. K2P channels allow potassium ions to pass from the inside of the cell to the outside thus helping the cell maintain its appropriate RMP. These channels have been implicated in playing roles in the response of cardiac and neuronal cells to substances such as drugs and anaesthetics as well as natural substances like hormones, neurotransmitters and changes in oxygen tension. An important feature of K2P channels is that once at the surface of the cell these channels are active and allow potassium to move from areas of high potassium concentration (inside the cell) to areas of low potassium concentration (outside the cell). Because these channels allow potassium to leak out of the cell once they are inserted into the cell membrane it is critical to closely regulate the number of K2P channels on the cell surface at any given time. Similarly it is important to understand how the cell increases or decreases the number of the channels at the cell surface in response to different environmental messages or needs. The work in my laboratory focuses on the different ways a cell can control the production and delivery of ion channels to the correct location within the cell. The focus of this proposal is on the mechanisms the cell uses to retrieve K2P channels from the cell surface and how this process can be disrupted or regulated. This is important as understanding the balance between channel delivery to and recovery from the cell surface will provide critical understanding of the mechanism by which cells control not only their RMP but their ability to respond to their environment and perform their cellular functions.