Grant: CIHR Fellowship

A cardiac arrhythmia is an electrical disturbance in the heart, which can cause a wide variety of potentially life threatening conditions. The root of these disturbances is a malfunction in the protein channels that open and close to transmit the bioelectric currents signaling each heartbeat. Different types of channels are responsible for triggering, sustaining or terminating these electric signals; an arrhythmia occurs when the opening or closing of one or more of these channels becomes mistimed. One of the key channels responsible for terminating the electrical signal is the voltage gated potassium channel, KCNQ1. This channel is regulated by a family of five much smaller accessory proteins, which physically associate with the channel's exterior. Each family member interacts with the channel differently to effect its movements and change its conducting properties, depending on the needs of the heart. These accessory proteins are necessary for healthy function; however, several inherited mutations in their genes can result in early or late termination of the heart's signaling, causing an arrhythmia to develop. In our project we aim to better understand the mechanism for how each of the different accessory proteins regulates KCNQ1. To achieve this we will combine a new crosslinking technique, electrophysiology and mass spectrometry to find and characterize the key sites of interaction between the channel and its different accessory proteins. This analysis will give us insights into the atomic level movements of the channel and how the different accessory subunits encourage or impede those movements to control the channel's properties. Our proposed experiments will fill crucial gaps in the knowledge of how these accessory subunits regulate KCNQ1 and ultimately cardiac function. This information will aid in designing better pharmaceuticals to help restore and maintain healthy electrical activity in the heart.