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.