Role of calpain in apoptosis

Abstract

Apoptosis, a form of programmed cell death that occurs under physiological as well as pathological conditions, is characterized by morphological and biochemical features. While the importance of caspases in apoptosis is established, several noncaspase proteases (Ca(2+)-dependent proteases) such as calpain may play a role in the execution of apoptosis. The calpain family consists of two major isoforms, calpain I and calpain II which require µM and mM Ca(2+) concentrations to initiate their activity. An increase in intracellular Ca(2+) level is thought to trigger a cascade of biochemical processes including calpain activation. Once activated, calpains degrade membrane, cytoplasmic and nuclear substrates, leading to the breakdown of cellular architecture and finally apoptosis. The activation of calpain has been implicated in neuronal apoptosis following spinal cord injuries and neurodegenerative diseases. This review focuses on calpain with an emphasis on its key role in the proteolysis of cellular protein substrates following apoptosis.

Keywords: Apoptosis; Calpain; Calpain Substrates.

Fig 1

Apoptosis in a motor neuron of the adult mouse spinal cord in a slice culture. A combination of propidium iodide (red) and Hoechst (blue) stained motor neurons. A. Motor neuron from freshly prepared slices (0 hour). B. Apoptotic motor neuron from slice cultured for 6 hours shows clear cell shrinkage as well as nuclear and chromatin condensation

Fig 2

Agarose gel electrophoresis of DNA isolated from adult spinal cord slices in culture. Lane 1: Markers presented as base pairs. Lane 2: High molecular weight DNA from fresh slices (0 hour). Lane 3: Nucleosomal DNA fragmentation in slices cultured for 24 hours.

Fig 3

Domain structure of calpain subunits. The large subunit and small subunit contain four and two domains, respectively. E-helix-loop-F helix (EF hands) located in domains III, IV and VI are calmodulin-like Ca²⁺ binding sites (Modified from reference 13).

Fig 4

Schematic autolysis/dissociation mechanism for the activation of calpain.

Fig 5

Domain structure of calpastatin (Modified from reference 13).

Fig 6

Calpain is activated by intracellular Ca²⁺ overload. Once activated, calpain hydrolyses its substrates in the cytosol, nucleus and membrane, resulting in apoptosis.