text: The effects of calcium on human cells are specific, meaning that different types of cells respond in different ways. However, in certain circumstances, its action may be more general. Ca ions are one of the most widespread second messengers used in signal transduction. They make their entrance into the cytoplasm either from outside the cell through the cell membrane via calcium channels (such as calcium-binding proteins or voltage-gated calcium channels), or from some internal calcium storages such as the endoplasmic reticulum and mitochondria. Levels of intracellular calcium are regulated by transport proteins that remove it from the cell. For example, the sodium-calcium exchanger uses energy from the electrochemical gradient of sodium by coupling the influx of sodium into cell (and down its concentration gradient) with the transport of calcium out of the cell. In addition, the plasma membrane Ca ATPase (PMCA) obtains energy to pump calcium out of the cell by hydrolysing adenosine triphosphate (ATP). In neurons, voltage-dependent, calcium-selective ion channels are important for synaptic transmission through the release of neurotransmitters into the synaptic cleft by vesicle fusion of synaptic vesicles.
  Calcium's function in muscle contraction was found as early as 1882 by Ringer. Subsequent investigations were to reveal its role as a messenger about a century later. Because its action is interconnected with cAMP, they are called synarchic messengers. Calcium can bind to several different calcium-modulated proteins such as troponin-C (the first one to be identified) and calmodulin, proteins that are necessary for promoting contraction in muscle.
  In the endothelial cells which line the inside of blood vessels, Ca ions can regulate several signaling pathways which cause the smooth muscle surrounding blood vessels to relax.  Some of these Ca-activated pathways include the stimulation of eNOS to produce nitric oxide, as well as the stimulation of K channels to efflux K and cause hyperpolarization of the cell membrane.  Both nitric oxide and hyperpolarization cause the smooth muscle to relax in order to regulate the amount of tone in blood vessels.  However, dysfunction within these Ca-activated pathways can lead to an increase in tone caused by unregulated smooth muscle contraction.  This type of dysfunction can be seen in cardiovascular diseases, hypertension, and diabetes.
  Calcium coordination plays an important role in defining the structure and function of proteins. An example a protein with calcium coordination is von Willebrand factor (vWF) which has an essential role in blood clot formation process. It was discovered using single molecule optical tweezers measurement that calcium-bound vWF acts as a shear force sensor in the blood. Shear force leads to unfolding of the A2 domain of vWF whose refolding rate is dramatically enhanced in the presence of calcium.