A hydrophobic barrier deep within the inner pore of the ​TWIK-1 K2P potassium channel

• Main Authors: Aryal, Prafulla, Abd Wahab, Firdaus, Bucci, Giovanna, Sansom, Mark, Stephen, Tucker
• Format: Article
• Language: English; English
• Published: Nature Publishing Group 2014
• Subjects: Q Science (General); RM Therapeutics. Pharmacology
• Online Access: http://irep.iium.edu.my/47584/1/47584.pdf; http://irep.iium.edu.my/47584/4/47584_A%20hydrophobic%20barrier%20deep_SCOPUS.pdf; http://irep.iium.edu.my/47584/; http://www.nature.com/ncomms/2014/140708/ncomms5377/full/ncomms5377.html

Recent X-ray crystal structures of the two-pore domain (K2P) family of potassium channels have revealed a unique structural architecture at the point where the cytoplasmic bundle-crossing gate is found in most other tetrameric K+ channels. However, despite the apparently open nature of the inner pore in the ​TWIK-1 ( K2P1/​KCNK1) crystal structure, the reasons underlying its low levels of functional activity remain unclear. In this study, we use a combination of molecular dynamics simulations and functional validation to demonstrate that ​TWIK-1 possesses a hydrophobic barrier deep within the inner pore, and that stochastic dewetting of this hydrophobic constriction acts as a major barrier to ion conduction. These results not only provide an important insight into the mechanisms which control ​TWIK-1 channel activity, but also have important implications for our understanding of how ion permeation may be controlled in similar ion channels and pores.