Seeing the “invisible” organization of calcium signaling in immune cells

Waves of calcium flowing in and out of cells are a universal mode of communication in mammalian cells including T cells. In T cells, calcium enters mainly through the calcium channel ORAI1, which is located in the outer cell membrane. The channel opens its gates when it is activated by a regulatory molecule that sits on the endoplasmic reticulum (ER), a network of membranes inside the cell. The calcium channel and its regulator can only interact at sites of close contact between the two membrane systems, which are known as ER-plasma membrane junctions.

When Dr. Zhang conducted as series of super-resolution microscopy studies to learn more about how these junctions support calcium signaling, she found that scaffolding proteins set up local barriers that corral ORAI1 within ER-plasma membrane junctions. She successfully established single molecule-tracking capabilities at a resolution of 70 nm (or about 1/100 of the diameter of a strand of hair), which allowed her to track individual molecules of ORAI1. However, the molecules that regulate ORAI channel activity are thought to localize within extremely small subregions of ER-plasma membrane junctions. These regions fall below the currently available maximum resolution and thus have been invisible so far. Therefore, a finer-grained picture of ORAI1 movements and its regulators within ER-plasma membrane junctions is needed to fully understand how ORAI1 activity is regulated.

Dr. Zhang plans to explore imaging techniques that can bring junction subregions into focus. Getting a clearer picture of the molecules that regulate the activity of calcium channels in T lymphocytes will provide potential targets for the development of drugs that modulate the activation status of T cells to fight infections and cancer more efficiently or to prevent inappropriate immune responses that underlie autoimmune diseases such as type 1 diabetes and rheumatoid arthritis.