Protein arginine methylation facilitates KCNQ channel-PIP2 interaction leading to seizure suppression

In the brain, cells called neurons transmit information along their length in the form of electrical signals. To generate electrical signals, ions move into and out of neurons through ion channel proteins – such as the KCNQ channel – in the surface of these cells, which open and close to control the electrical response of the neuron. Abnormally intense bursts of electrical activity from many neurons at once can cause seizures such as those experienced by people with epilepsy. A significant proportion of patients do not respond to current anti-seizure medications. Openers of KCNQ channels have emerged as a potential new class of anti-epileptic drugs. A better understanding of how KCNQ channels work, and how their opening by PIP2lipid signals is regulated, could help to develop more effective therapies for epilepsy. A process called methylation controls many biological tasks by changing the structure of key proteins inside cells. Although methylation occurs throughout the brain, its role in controlling how easily neurons are activated (a property known as “excitability”) remains unclear. Kim, Jeong, Kim, Jung et al. now show that a protein called Prmt1 methylates the KCNQ channels in mice, and that this methylation is essential for suppressing seizures. Mice born without the Prmt1 protein developed epileptic seizures and the KCNQ channels in their neurons featured a reduced level of methylation. However, increasing the amount of PIP2 in these neurons restored their excitability back to normal levels. The methylation of KCNQ channel proteins increases their affinity for PIP2, which is critical to open KCNQ channels. Kim et al. propose that these “opening” controllers balance the action of known “closers” of KCNQ channels to maintain neurons in a healthy condition. In future, Kim et al. plan to investigate whether methylation affects the activity of other ion channels controlled by PIP2. Such experiments will complement a more widespread investigation into other ways in which the Prtmt1 protein may control the activity of neurons.