Ca2+ regulates a very large number of physiologic processes that are as diverse as proliferation, neural signaling, learning, contraction, secretion, and fertilization, so regulation of intra cellular Ca2+ is of great importance. The free Ca2+ concentration in the cytoplasm at rest is maintained at about 100 nmol/L. The Ca2+ concentration in the interstitial fluid is about 12,000 times the cytoplasmic concentration (ie, 1,200,000 nmol/L), so there is a marked inwardly directed concentration gradient as well as an inwardly directed electrical gradient. Much of the intracellular Ca2+ is stored at relatively high concentrations in the endoplasmic reticulum and other organelles (Figure1), and these organelles provide a store from which Ca2+ can be mobilized via ligand-gated channels to increase the concentration of free Ca2+ in the cytoplasm. Increased cytoplasmic Ca2+ binds to and activates calcium-binding proteins. These proteins can have direct effects in cellular physiology, or can activate other proteins, commonly protein kinases, to further cell signaling pathways.
Fig1. Ca2+ handling in mammalian cells. Ca2+ can enter the cell via a variety of channel types. In addition, Ca2+ is stored in the endoplasmic reticulum (and, to a lesser extent in the mitochondrion) where it can be released to alter free Ca2+ concentration in the cytoplasm. Free Ca2+ can be bound by proteins that then have a variety of downstream physiologic effects. Ca2+ can be removed from the cytoplasm by ATPases in the endoplasmic reticulum or at the plasma membrane, or via Na, Ca exchangers (not shown).
Ca2+ can enter the cell from the ECF, down its electro chemical gradient, through many different Ca2+ channels. Some of these are ligand-gated and others are voltage-gated. Stretch-activated channels exist in some cells as well.
Many second messengers act by increasing the cytoplasmic Ca2+ concentration. The increase is produced by releasing Ca2+ from intracellular stores—primarily the endoplasmic reticulum—or by increasing the entry of Ca2+ into cells, or by both mechanisms. IP3 is the major second messenger that causes Ca2+ release from the endoplasmic reticulum through the direct activation of a ligand-gated channel, the IP3 receptor. In effect, the generation of one second messenger (IP3 ) can lead to the release of another second messenger (Ca2+). In many tissues, transient release of Ca2+ from internal stores into the cytoplasm triggers opening of a population of Ca2+ channels in the cell membrane (store-operated Ca2+ channels; SOCCs). The resulting Ca2+ influx replenishes the total intracellular Ca2+ supply and refills the endoplasmic reticulum. Recent research has identified the physical relationships between SOCCs and regulatory interactions of proteins from the endoplasmic reticulum that gate these channels.
As with other second messenger molecules, the increase in Ca2+ within the cytosol is rapid, and is followed by a rapid decrease. Because the movement of Ca2+ outside of the cytosol (ie, across the plasma membrane or the membrane of the internal store) requires that it move up its electrochemical gradient, it requires energy. Ca2+ movement out of the cell is facilitated by the plasma membrane Ca2+ ATPase. Alternatively, it can be transported by an antiport that exchanges three Na+ for each Ca2+ driven by the energy stored in the Na+ electrochemical gradient. Ca2+ movement into the internal stores is through the action of the sarcoplasmic or endoplasmic reticulum Ca2+ ATPase, also known as the SERCA pump.
