...as usual.

The problem is complicated by observations that calpain sensitivity to calcium flux is increased in the presence of phospholipids (such as those released by early lipolysis) by up to an order of magnitude. Put it all together, and ischemia and early reperfusion are a scenario in which calpain can really get its freak on.

When calcium concentrations are sufficient to activate calpain, the first thing calpain cuts is itself. (Talk about a sick puppy.) That is to say, it undergoes autoproteolysis, which makes the calpain more responsive to calcium. Differences in calcium requirements between the two isoforms predict that mu-calpain (in neurons) but not m-calpain (in glia) will undergo autoproteolysis and activate...and this prediction has been borne out. And, as you may have guessed, there is some evidence that the neurons richest in calpain tend to be those neurons most vulnerable to ischemic insult.

Figure: Calpain gets activated during ischemia, when the glutamate surge results in calcium overloading.