Calpain-1 and Calpain-2: The Yin and Yang of Synaptic Plasticity and Neurodegeneration

Many signaling pathways participate in both synaptic plasticity and neuronal degeneration. While calpains participate in these phenomena, very few studies have evaluated the respective roles of the two major calpain isoforms in the brain, calpain-1 and calpain-2. We review recent studies indicating that calpain-1 and calpain-2 exhibit opposite functions in both synaptic plasticity and neurodegeneration. Calpain-1 activation is required for the induction of long-term potentiation (LTP) and is generally neuroprotective, while calpain-2 activation limits the extent of potentiation and is neurodegenerative. This duality of functions is related to their associations with different PDZ-binding proteins, resulting in differential subcellular localization, and offers new therapeutic opportunities for a number of indications in which these proteases have previously been implicated.