Cooperative and acute inhibition by multiple C-terminal motifs of L-type Ca2+ channels

All cells need calcium ions to stay healthy, but having too many calcium ions can interfere with important processes in the cell and cause severe problems. Proteins known as calcium channels on the cell surface allow calcium ions to flow into the cell from the surrounding environment. Cells carefully control the opening and closing of these channels to prevent too many calcium ions entering the cell at once. CaV1.3 channels are a type of calcium channel that are important for the heart and brain to work properly. Defects in CaV1.3 channels can lead to irregular heart rhythms and neurodegenerative diseases such as Parkinson’s disease. Studies have shown that part of the CaV1.3 channel that sits inside the cell – known as the “tail” – responds to increases in the levels of calcium ions inside the cell by closing the channel. The tail region of CaV1.3 contains three modules, but how these modules work together to regulate channel activity is not clear. Liu, Yang et al. investigated whether the three modules need to be physically connected to each other in the channel protein. For the experiments, several versions of the protein were constructed with different combinations of tail modules being directly linked as part of the same molecule or present as separate molecules. When any two modules were directly linked, the third module could bind to them and this was enough to close the CaV1.3 channel. However, the channel did not close if the modules were totally isolated from each other as three separate molecules. Certain types of neurons in the brain produce electrical signals in a rhythmic fashion that depends on CaV1.3 channels. In Parkinson’s disease, increased movement of calcium ions into these neurons via CaV1.3 channels interferes with the rhythms of the signals and can cause these cells to die. Liu, Yang et al. performed computer simulations to analyse the effects of closing CaV1.3 channels in these neurons. The results suggest that this can restore normal rhythms of electrical activity and prevent these cells from dying. The next step is to understand the molecular details of how the tail region closes CaV1.3 channels and its role in healthy and diseased cells. This may lead to new ways to block CaV1.3 channels in different types of diseases.