AI Article Synopsis
- KCNQ family potassium channels (KCNQ1-5) in various tissues require phosphatidylinositol 4,5-bisphosphate (PIP) for their voltage activation, and PIP helps couple the voltage sensor domain (VSD) to the pore of the channel in KCNQ1.* -
- A compound called CP1 was discovered to mimic PIP's role by interacting with the same crucial amino acid cluster needed for VSD-pore coupling, albeit with different effects on KCNQ channel function.* -
- The study demonstrated that CP1 can revert prolonged action potentials in heart cells caused by drugs to normal levels, suggesting its potential as a basis for new anti-arrhyth
Article Abstract
KCNQ family K channels (KCNQ1-5) in the heart, nerve, epithelium and ear require phosphatidylinositol 4,5-bisphosphate (PIP) for voltage dependent activation. While membrane lipids are known to regulate voltage sensor domain (VSD) activation and pore opening in voltage dependent gating, PIP was found to interact with KCNQ1 and mediate VSD-pore coupling. Here, we show that a compound CP1, identified in silico based on the structures of both KCNQ1 and PIP, can substitute for PIP to mediate VSD-pore coupling. Both PIP and CP1 interact with residues amongst a cluster of amino acids critical for VSD-pore coupling. CP1 alters KCNQ channel function due to different interactions with KCNQ compared with PIP. We also found that CP1 returned drug-induced action potential prolongation in ventricular myocytes to normal durations. These results reveal the structural basis of PIP regulation of KCNQ channels and indicate a potential approach for the development of anti-arrhythmic therapy.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367283 | PMC |
| http://dx.doi.org/10.1038/s42003-020-1104-0 | DOI Listing |
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