KCNE and long QT syndrome

Although many of us blame an erratic heart beat on one too many cups of coffee or a spike in anxiety, it can also be the fault of a peculiar ion channel. To circulate blood around the body properly, a healthy heart needs to repeatedly and regularly contract and relax. Did you know that a dysregulation of potassium ion flow in cardiac tissue can lead to a disruption of the normal contraction of the heart known as Long QT Syndrome (LQTS)? (Fig. 1).

  Figure 1:  A comparison of a normal electrocardiogram to that of a person with Long-QT syndrome. In Long-QT, the time it takes for the heart to “reset” after a depolarization is extended. (Source: MMRI)

Figure 1: A comparison of a normal electrocardiogram to that of a person with Long-QT syndrome. In Long-QT, the time it takes for the heart to “reset” after a depolarization is extended. (Source: MMRI)

 

Symptoms associated with LQTS include fainting, dizziness, stroke, and even cardiac arrest. While approximately 200,000 patients are diagnosed with LQTS per year according to the NIH, many more suffer the symptoms without a formal diagnosis. One of the ion channels responsible for maintaining proper potassium balance and keeping your heartbeat regular is KCNQ1.

Potassium Voltage-Gated Channel Subfamily Q Member 1 (KCNQ1) is an ion channel that allows potassium to exit cardiac muscle cells. At the initiation of a heartbeat, sodium channels open and allow sodium to rapidly enter the cardiac cells. This influx of positive charge depolarizes the cell and causes a substantial shift in electrical potential. Soon after, it is the job of ion channels like KCNQ1 to allow the passage of potassium out of the cell and repolarize the cardiac cells in preparation for another contraction. When KCNQ1 is mutated or cannot function properly, the time it takes for the cardiac cell to repolarize is extended, leading arrhythmia characteristic of LQTS.

KCNQ1 is especially noteworthy because its ion channel activity is regulated directly by its interactions with subunits of the related KCNE family, as highlighted in a 2016 review by Geoffrey Abbot (PMC4917010). Most ion channels function within particular voltage ranges and pass ions at a fixed rate. KCNQ1 alone is able to pass potassium ions in a voltage-dependent manner across the plasma membrane. However, only when KCNQ1 is associated with the subunit KCNE1 is it able to pass current at the elevated voltages experienced during a cardiac depolarization. Furthermore, the function of KCNQ1 is completely changed by association with a different subunit, KCNE3. The KCNQ1-KCNE3 complex is found in intestinal tissue and the lungs. Here, KCNQ1 is held open by KCN3, loses its voltage dependence, and relies on driving force of concentration gradients to pass potassium ions. This helps it to control both potassium and chloride homeostasis in these organs.

Knowing that KCNQ1 has varied functions depending on how it associates with its subunits, it is important to observe how this affects its structure as well. Recent studies on the crystal structure of KCNQ1 both alone and associated with KCNE1 give us new insight on how changes in the channel’s structure affect its ability to pass potassium ions across the plasma membrane (Hasani et al. 2018; PMID: 29444113). Additionally, knowing the structure allows us to potentially target defective KCNQ1-KCNE1 with drug treatments in order to correct the symptoms of LQTS.

 

Post by Grant Daskovich and Anne Carlson

Anne Carlson