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Title: Functional role of the background potassium channel K2P15.1
Author: Roncoroni, Laura
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2012
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hK2P15.l, a two-pore domain potassium channel (K2P) was first identified in 2001 by four independent groups (Ashmole et aI., 2001; Karschin et aI., 2001; Kim and Gnatenco, 2001; Vega-Saenz de Miera et aI., 2001). Although hK2P15.l fails to show functional current in recombinant expression systems it was included in the Acid Sensitive subgroup (TASK) of K2P channels primarily due to its sequence homology with the other two family members K2P3.l and K2P9.1. K2P channels are active over physiological voltage ranges resulting in constituent leak of K+ from the cell. These channels are fundamental in setting and regulating the resting membrane potential of cells, are regulated by physiological stimuli and play key roles in several physiological processes. At the messenger RNA level, KCNK15 has a wide tissue distribution and shows high levels of expression specifically in pancreas and adrenal glands (Ashmole et aI., 2001; Kim and Gnatenco, 2001). However, while hK2P 15.1 is anticipated to play an important role in both adrenal and pancreatic function to date the physiological function and pharmacological profile of this channel has been elusive (Ashmole et aI., 2001; Karschin et aI., 2001; Kim and Gnatenco, 2001). Data presented here provide the first evidence of hK2P15.1 retention within the ER and inability to achieve surface expression under control conditions. Significantly, hK2P15.l does localise to other intracellular organelles including the nuclear membrane, mitochondria, endocytic vesicles and lysosomes. Consequently, the physiological role of hK2P15.1 was examined. By analysing hK2P15.1 post-translational modification and binding proteins, the retention of hK2P 15.1 within the ER was found to be dependent on its interaction with BIP. BIP is a chaperon protein involved in cellular response to stress. Removal of BIP-binding or cellular stress enable hK2P15.l release from the ER and targeting at the cell membrane. This links the BIP-dependent ER retention of hK2P 15.1 with the role of BIP in response to cellular stress. Hence, hK2P 15.1 is here suggested to play a role in the control of mitochondrial potential and activity in control conditions and to achieve surface expression and control the cell membrane potential under conditions of cellular stress.
Supervisor: O'kelly, Ita ; Wilson, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QH301 Biology