Cytosolic Ca2+ Buffers Are Inherently Ca2+ Signal Modulators.

For precisely regulating intracellular Ca2+ signals in a time- and space-dependent manner, cells make use of various components of the "Ca2+ signaling toolkit," including Ca2+ entry and Ca2+ extrusion systems. A class of cytosolic Ca2+-binding proteins termed Ca2+ buffers serves as modulators of such, mostly short-lived Ca2+ signals. Prototypical Ca2+ buffers include parvalbumins (α and β isoforms), calbindin-D9k, calbindin-D28k, and calretinin. Although initially considered to function as pure Ca2+ buffers, that is, as intracellular Ca2+ signal modulators controlling the shape (amplitude, decay, spread) of Ca2+ signals, evidence has accumulated that calbindin-D28k and calretinin have additional Ca2+ sensor functions. These other functions are brought about by direct interactions with target proteins, thereby modulating their targets' function/activity. Dysregulation of Ca2+ buffer expression is associated with several neurologic/neurodevelopmental disorders including autism spectrum disorder (ASD) and schizophrenia. In some cases, the presence of these proteins is presumed to confer a neuroprotective effect, as evidenced in animal models of Parkinson's or Alzheimer's disease.