Author response: Unnatural amino acid photo-crosslinking of the IKs channel complex demonstrates a KCNE1:KCNQ1 stoichiometry of up to 4:4

The membrane that surrounds heart muscle cells contains specialized channels that can open and close to control the movements of charged ions into and out of the cell. This ion flow generates the electrical signals that stimulate the heart muscle to contract for each heart beat. Different ion channels influence different steps in the initiation and termination of each electrical signal. For example, the IKs ion channel complex helps to return the cell to a resting state so the heart muscle can relax. This allows chambers of the heart to fill with blood before the next beat pumps blood throughout the body. Mutations that affect IKs cause serious heart conditions that affect heart rhythm, such as Long QT Syndrome. The IKs complex consists of channels that are each made of four copies of a protein called KCNQ1, through which potassium ions exit the cell. This channel opens in response to changes in the voltage across the cell membrane (known as the “membrane potential”). A small protein subunit called KCNE1 also makes up part of the complex, but it was not clear how many KCNE1 molecules combine with KCNQ1 to form a working channel complex. Several previous studies have reported two different results: that the KCNQ1 channel complex only exists with two KCNE1 molecules, or that the association is flexible, allowing the complex to contain up to four KCNE1 subunits. Murray et al. have now constructed IKs fusion channels out of different numbers of KCNQ1 and KCNE1 molecules to investigate how different KCNQ1:KCNE1 ratios affect how the channel works. Measuring the responses of these modified channels in mammalian cells revealed that channels with four KCNE1 subunits conducted ions better than channels with one or two KCNE1s. The channels containing fewer KCNE1s also opened at lower membrane potentials and after a shorter delay following a change in the membrane potential. Further experiments also supported the theory that up to four independent KCNE1 subunits may be easily added to the IKs ion channel complex. Murray et al. suggest that by being able to form channel complexes containing different numbers of KCNE1 subunits, cells can more flexibly control the rate at which ions flow out of the heart cells to tune the electrical signals that trigger each heart beat. The next challenges will be to determine the composition of the IKs channel complex in adult heart cells and to investigate how the complex might change with disease.

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