A novel treatment for arrhythmias via the control of the degradation of ion channel proteins

Abstract

Although there are many reports on the regulation of ion channel expression in transcription and translation, few drugs have been studied to influence post-translational modification of ion channel proteins. The Kv1.5 channel is a potassium ion channel expressed in atrial muscle, belongs to the voltage-gated K+ channel superfamily, and forms an ultrarapid delayed rectifier potassium ion current. It is important to understand the fate of these channel proteins, as cardiac Kv1.5 mutations can cause arrhythmias. Disruption of quantitative and qualitative control mechanisms of channels leads to stagnation and degradation of intracellular channel proteins. As a result, ion channel proteins are not transported to the cell membrane and are involved in the development of atrial fibrillation. This review takes the Kv1.5 channel as an example and focuses on the degradation mechanism of ion channel proteins, and discusses its application to the treatment of arrhythmia by drugs that control the mechanism of ion channel protein degradation.Ion channels are membrane proteins responsible for the formation of resting membrane potential and action potential of the myocardium. The mRNA transcribed from the nuclear DNA is spliced when passing through the nuclear pore and translocating to the cytoplasm, and then an ion channel protein is formed on the ribosome as a protein having a primary structure. The ion channel protein having a primary structure undergoes post-translational modification such as folding and sugar chain modification via the endoplasmic reticulum and Golgi apparatus, and is then transported to the cell membrane via microtubules. In addition, the transported ion channel proteins function by binding to anchor proteins present on the membrane.1, 2 To date, there have been many reports on the regulation of ion channel expression in transcription and translation, but few studies on drugs that affect post-translational modification of ion channel proteins. The Kv1.5 channel is a potassium ion channel expressed in atrial muscle, belongs to the voltage-gated K+ channel superfamily and forms ultrarapid delayed rectifier K+ currents (IKur) in the myocardium.3 Since mutations in the cardiac Kv1.5 can cause arrhythmias,4 it is important from a cell biology perspective to understand the fate of these channel proteins. Disruption of the quantitative and qualitative control mechanisms of the channel due to innate and acquired factors leads to stagnation and degradation of the channel protein in the cell. As a result, ion channel proteins are not transported to the cell membrane and are involved in the development of atrial fibrillation.5 This review takes the Kv1.5 channel as an example and focuses on the degradation mechanism of ion channel proteins, and describes its application to the treatment of arrhythmias by drugs that control the mechanism of ion channel protein degradation.