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.