Calcium plays a central role in signal transduction in cells thereby activating cellular growth and development. External signals (Growth factors, neurotransmitters, hormones) arriving at the cell activate plasma membrane receptors to initiate cell signaling pathways. One of the consequences of this signaling is increased intracellular calcium concentration. Surges in free cytosolic Ca2+ concentration are a result of the flow of Ca2+ from the extracellular space or from sequestered intracellular stores.
The endoplasmic reticulum (ER) is a major site for sequestered Ca2+ ions. Calcium that is accumulated into intracellular stores via Ca2+ pumps can be released into the cytosol by inositol 1,4,5-trisphosphate (IP3) receptors and ryanodine receptors. Extracellular Ca2+ enters the cell through a variety of plasma-membrane Ca2+ channels- Calcium release activated channels (CRAC), Voltage gated Calcium channels (VGCC) and channels for neurotransmitters like glutamate, serotonin and acetylcholine that are permeable to calcium. Depletion of intracellular Ca2+ stores triggers plasma membrane calcium channel activity.
In addition to Ca2+ pumps, exchangers and channels, soluble calcium binding proteins like calmodulin play an important role in maintaining intracellular calcium levels. Calmodulin (CaM) is a primary Ca2+-binding protein found in all eukaryotic cells. It couples the intracellular Ca2+ signal to many essential cellular events by binding and regulating the activities of different proteins and enzymes in a Ca2+-dependent manner e.g. Ca2+/calmodulin-dependent protein kinases (CaM-kinases). Other important calcium binding proteins include calsequestrin (CASQ) and calreticulin (CALR) found in more specific subcellular locations. CASQ is by far the most abundant Ca2+binding protein in the sarcoplasmic reticulum (SR) of skeletal and cardiac muscle.
The increase in cytosolic Ca2+ triggers a signaling cascade culminating in the regulation of transcription factors like nuclear factor of activated T-cells (NFAT), cAMP response element-binding protein (CREB) and Histone deacetylase (HDAC) which in turn trigger gene expression and therefore several cellular events. In addition Ca2+ plays a central role in muscle contraction and apoptosis.
The calcium signaling pathway highlights the key molecular events involved in calcium activated signal transduction.