Zamponi, Gerald (University of Calgary)

Purpose

Calcium ions are important for a variety of aspects of physiological function including memory, transmission of nerve signals, and the generation of the heart beat. Calcium entry into cells is mediated by calcium channels, a family of proteins which are embedded in the cell membrane and allow calcium ions to pass through them. Because excessive calcium levels can be toxic to cells, the amount of calcium entering through these channels is tightly regulated. Given their pivotal roles, it is therefore critical to understand how the calcium channels function at the molecular level, and how cells regulate the amount of calcium channel protein that is present. Among the various types of calcium channels, one particularly important class are the L-type calcium channels which are vital for the activation of genes and calcium dependent enzymes. In this application, we propose to investigate the molecular basis that governs the trafficking of L-type calcium channels from the inside of the cells where they are synthesized and assembled, to the cell membrane where they regulate calcium entry. We also will determine how cellular activity regulates how long the channels remain at the cell surface. We will investigate how regulatory proteins and auxiliary calcium channels subunits that form part of the channel affect this trafficking. We will use a combination of state of the art experimental techniques to tackle our objectives. These include molecular biology, biochemistry, optogenetics and electrical recordings from calcium channels in model systems and in neurons. Specifically, we will manipulate the function of calcium channels and their regulatory proteins via DNA technology, and then examine how this affects their assembly, trafficking, and membrane stability. Altogether, this work will provide novel insights about a fundamental biological process that is applicable across a wide range of species.