KCNE1 tunes the sensitivity of KV7.1 to polyunsaturated fatty acids by moving turret residues close to the binding site

The muscle cells in the heart must contract and relax in a coordinated way for the heart to pump blood efficiently around the body. Different ions flow in and out of these cells, which are known as cardiomyocytes, to control when they contract and relax. The ions enter and leave by passing through channel proteins in each cell’s membrane. People with mutations in the genes that encode these channel proteins are often prone to irregular heartbeats and may suddenly die because their heart stops pumping blood effectively. Drugs that can restore the function of mutated ion channels are considered an attractive new avenue for treating the irregular heartbeats and preventing the sudden deaths. Yet a poor understanding of how the other proteins that interact with these channels may reduce the effect of these drugs has hampered their development. In 2015, researchers showed that some polyunsaturated fatty acids could help restore a normal heartbeat via an effect on the IKs channel, one of the ion channels that regulate the electric activity in cardiomyocytes. But, a protein called KCNE1 – which forms part of the IKs channel – reduced the effect of these fatty molecules via an unknown mechanism. Now, Larsson et al. – who are three of the researchers involved in the 2015 study – report how KCNE1 reduces the effect of polyunsaturated fatty acids on the IKs channel. The experiments involved mutated human IKs channels produced in the egg cells of African clawed frogs – a popular model system for a wide variety of biological studies. Larsson et al. found that flexible loop-like part of the IKs channel has an overall negative charge that attracts positively charged hydrogen ions to the polyunsaturated fatty acid. This masks the electrical change of the fatty acid so that it no longer has any effect on the IKs channel. Yet, this phenomenon only occurs when KCNE1 is present, suggesting that KCNE1 moves specific parts of the loop close to the polyunsaturated fatty acid. Several ion channels in cardiomyocytes are made from multiple subunits. Understanding how some of these subunits alter the effect of drugs will help scientists to develop drugs that efficiently act on these ion channels. Such drugs may offer new treatments for irregular heartbeats and prevent the sudden deaths. But as with all new drugs, extensive testing and clinical trials will be needed before anything reaches the clinic.