WHAT IS A CALPAIN?
- A calpain is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases (proteolytic enzymes) expressed ubiquitously in mammals and many other organisms.
- Calpains constitute the C2 family of protease clan CA in the MEROPS database.
- The calpain proteolytic system includes the calpain proteases, the small regulatory subunit CAPNS1, also known as CAPN4, and the endogenous calpain-specific inhibitor, calpastatin.
- The history of calpain originates in 1964, when calcium-dependent proteolytic activities caused by a â€œcalcium-activated neutral proteaseâ€ (CANP) were detected in brain, lens of the eye and other tissues.
- In the late 1960s the enzymes were isolated and characterised independently in both rat brain and skeletal muscle.
- These activities were caused by an intracellular cysteine protease not associated with the lysosome and having an optimum activity at neutral pH, which clearly distinguished it from the cathepsin family of proteases.
- The calcium-dependent activity, intracellular localization, along with the limited, specific proteolysis on its substrates, highlighted calpainâ€™s role as a regulatory, rather than a digestive protease.
- When the sequence of this enzyme became known, it was given the name calpain, to recognize it as a hybrid of two well-known proteins at the time, the calcium-regulated signaling protein, calmodulin, and the cysteine protease of papaya, papain.
- Shortly thereafter, the activity was found to be attributable to two main isoforms, dubbed Î¼("mu")-calpain and m-calpain (a.k.a. calpain I and II), that differed primarily in their calcium requirements in vitro.
- Their names reflect the fact that they are activated by micro- and nearly millimolar concentrations of Ca2+within the cell, respectively.
- To date, these two isoforms remain the best characterized members of the calpain family.
- Structurally, these two heterodimericisoforms share an identical small (28k) subunit (CAPNS1 (formerly CAPN4)), but have distinct large (80k) subunits, known as calpain 1 and calpain 2 (each encoded by the CAPN1 and CAPN2 genes, respectively).
- The structural and functional diversity of calpains in the cell is reflected in their involvement in the pathogenesis of a wide range of disorders.
- At least two well known genetic disorders and one form of cancer have been linked to tissue-specific calpains.
- When defective, the mammalian calpain 3 (also known as p94) is the gene product responsible for limb-girdle muscular dystrophy type 2A, calpain 10 has been identified as a susceptibility gene for type II diabetes mellitus, and calpain 9 has been identified as a tumor suppressor for gastric cancer.
- Moreover, the hyperactivation of calpains is implicated in a number of pathologies associated with altered calcium homeostasis such as Alzheimerâ€™s disease, and cataract formation, as well as secondary degeneration resulting from acute cellular stress following myocardial ischemia, cerebral (neuronal) ischemia, traumatic brain injury and spinal cord injury.
- Excessive amounts of calpain can be activated due to Ca2+ influx after cerebrovascular accident (during the ischemic cascade) or some types oftraumatic brain injury such as diffuse axonal injury.
- Increase in concentration of calcium in the cell results in calpain activation, which leads to unregulated proteolysis of both target and non-target proteins and consequent irreversible tissue damage.
- Excessively active calpain breaks down molecules in the cytoskeleton such as spectrin, microtubule subunits, microtubule-associated proteins, and neurofilaments.
- It may also damage ion channels, other enzymes, cell adhesion molecules, and cell surface receptors.
- This can lead to degradation of the cytoskeleton and plasma membrane.
- Calpain may also break down sodium channels that have been damaged due to axonal stretch injury, leading to an influx of sodium into the cell.
- This, in turn, leads to the neuron's depolarization and the influx of more Ca2+.
- A significant consequence of calpain activation is the development of cardiac contractile dysfunction that follows ischemic insult to the heart.
- Upon reperfusion of the ischemic myocardium, there is development of calcium overload or excess in the heart cell (cardiomyocytes). This increase in calcium leads to activation of calpain.