A polyunsaturated fatty acid (PUFA; bronze) bound between two parts (red and blue) in the pore domain (purple) of a KCNQ1 channel. Image credit: H. Peter Larsson, UCSF Chimera 1.14 software, PDB ID: 8SIK
Travelling through the heart are waves of electrical activity that cause muscle cells to contract and pump blood around the body. The waves are generated by charged ions which flow via tiny channels in and out of the muscle cells. This electrical activity spreads quickly from one cell to the next to make sure all the muscle cells contract at the right time. When these ion channels are compromised, this can lead to heart problems such as long QT syndrome (LQTS).
In patients with LQTS, electrical activity in the heart does not follow the typical rhythm, which can result in an irregular heartbeat and lead to cardiac arrest. The most common cause of LQTS is mutations in the channel KCNQ1, which allows potassium ions to flow out of heart muscle cells. This outflux of potassium restores the electrical charge inside the cell so that it is ready to receive another electrical wave and contract at the right time.
Current treatments for LQTS do not target KCNQ1 channels directly and have side effects. An alternative approach could be to use a group of molecules called polyunsaturated fatty acids (or PUFAs for short) which increase the flow of ions that pass through KCNQ1. However, it is not fully understood how PUFAs achieve this.
Previous research showed that PUFAs activate KCNQ1 via two independent sites: one at the voltage sensor which decides whether the channel is open or closed (Site I), and another at the pore domain ions pass through (Site II). While it is well understood how PUFAs activate the channel at Site I, little is known about the activation mechanism that occurs at Site II.
To investigate, Golluscio et al. modified egg cells from the frog Xenopus laevis to express KCNQ1 channels. Experiments investigating the electrical properties of KCNQ1 revealed that the selective filter in the pore domain – which permits potassium but no other ions to pass through – is usually unstable. However, PUFAs help to stabilize this filter, causing KCNQ1 to stay open more often and allow potassium ions to flow out of muscle cells.
The findings of Golluscio et al. suggest that PUFAs could represent an important therapeutic tool to treat LQTS and potentially other cardiac disorders. However, further studies in heart cells, animals and eventually humans will be required to confirm this conclusion.
