Grant: Operating Grant

Every beat of our heart requires cardiac muscle tissue to contract. This contraction is a finely orchestrated process, whereby many molecular events take place in each cardiac muscle cell. One crucial signal consists of calcium ions. Calcium ions are small molecules that play important roles in many different cells in our bodies. They are known primarily for their role in maintining bone structure, but they also play a key role in the contraction of muscle: just prior to each contraction, calcium ions flow from the outside of the cell to the inside, and from one compartment of the cell to another. This simple 'flux' of calcium is what then triggers the cell to contract. The basic principle of using calcium is simple and elegant. Every cell and cellular compartment is surrounded by a membrane, and calcium ions cannot pass through these. However, particular proteins, named 'calcium channels' can form pores through the membrane. These pores can open and close, and thus decide when calcium can pass through or stay on one side. It is of the utmost importance that these pores function properly: anything that goes wrong with opening or closing of the pore, will lead to either too much or too little calcium inside the proper compartment. This will directly influence the contraction of the heart, and lead to cardiac arrhythmias and even sudden cardiac death. In this grant proposal, we study such particular calcium channels. We particularly focus on how genetic mutations, known to result in cardiac arrhythmias, can cause faulty channels, and we study molecules that can alter the behavior of the pores. As such, we gain fundamental insights into disease mechanisms, and also try to devise new small molecules (drugs) to treat cardiac arrhythmias.