also occur in cells at rest (i.e. cells that have not been stimulated by an action potential). This occurs roughly 100 times every second in each cell and is a result of Ca2+ concentration being too high. An increase in Ca2+ within the SR is thought to bind to Ca2+ sensitive sites on the inside of the RyR causing the channel to open. As well as this, a protein called calsequestrin (found within the SR) detaches from the RyR, when calcium concentration is too high, again allowing the channel to open (see sarcoplasmic reticulum for more details). Similarly, a decrease in Ca2+ concentration within the SR has also proven to lower RyR sensitivity. This is thought to be due to the calsequestrin binding more strongly to the RyR, preventing it from opening and decreasing the likelihood of a spontaneous spark. Calcium after release There are roughly 10,000 clusters of ryanodine receptors within a single cardiac cell, with each cluster containing around 100 ryanodine receptors. During a single spontaneous spark, when Ca2+ is released from the SR, the Ca2+ diffuses throughout the cell. As the RyRs in the heart are activated by Ca2+, the movement of the Ca2+ released during a spontaneous spark, can activate other neighbouring RyRs within the same cluster. However, there usually isn't enough Ca2+ present in a single spark to reach a neighbouring cluster of receptors. The calcium can, however, signal back to the DHPR causing it to close and preventing further influx of calcium. This is known as negative feedback. An increase in Ca2+ concentration within the cell or the production of a larger spark, can lead to a large enough calcium released that the neighbouring cluster can be activated by the first. This is known as spark-induced spark activation and can lead to a Ca2+ wave of calcium release spreading across the cell. During evoked Ca2+ sparks, all clusters of ryanodine receptors, throughout the cell are activated at almost exactly the same time. This produces an increase in Ca2+ concentration across the whole cell (not just locally) and is known as a whole cell Ca2+ transient. This Ca2+ then binds to a protein, called troponin, initiating contraction, through a group of proteins known as myofilaments. In smooth muscle cells, the Ca2+ released during a spark is used for muscle relaxation. This is because, the Ca2+ that enters the cell via the DHPR in response to