Physiol Rev. 1999 Jul;79(3):661-82. doi: 10.1152/physrev.1999.79.3.661.


Intracellular Ca2+ is normally maintained at submicromolar levels but increases during many forms of cellular stimulation. This increased Ca2+ binds to receptor proteins such as calmodulin (CaM) and alters the cell's metabolism and physiology. Calcium-CaM binds to target proteins and alters their function in such a way as to transduce the Ca2+ signal. Calcium-free or apocalmodulin (ApoCaM) binds to other proteins and has other specific effects. Apocalmodulin has roles in the cell that apparently do not require the ability to bind Ca2+ at all, and these roles appear to be essential for life. Apocalmodulin differs from Ca2+-CaM in its tertiary structure. It binds target proteins differently, utilizing different binding motifs such as the IQ motif and noncontiguous binding sites. Other kinds of binding potentially await discovery. The ApoCaM-binding proteins are a diverse group of at least 15 proteins including enzymes, actin-binding proteins, as well as cytoskeletal and other membrane proteins, including receptors and ion channels. Much of the cellular CaM is bound in a Ca2+-independent manner to membrane structures within the cell, and the proportion bound changes with cell growth and density, suggesting it may be a storage form. Apocalmodulin remains tightly bound to other proteins as subunits and probably hastens the response of these proteins to Ca2+. The overall picture that emerges is that CaM cycles between its Ca2+-bound and Ca2+-free states and in each state binds to different proteins and performs essential functions. Although much of the research focus has been on the roles of Ca2+-CaM, the roles of ApoCaM are equally vital but less well understood.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Sequence / genetics
  • Animals
  • Calcium-Binding Proteins / metabolism
  • Calmodulin / genetics*
  • Calmodulin / physiology*
  • Humans
  • Ion Channels / metabolism
  • Molecular Sequence Data
  • Receptors, Cell Surface / metabolism


  • Calcium-Binding Proteins
  • Calmodulin
  • Ion Channels
  • Receptors, Cell Surface