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

Abstract

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.

Keywords: calpain; learning; neurodegeneration; neuroprotection; plasticity; protein synthesis.

Figure 1. Opposite functions of calpain-1&2 in synaptic plasticity

Calpain-1 is rapidly stimulated by the calcium influx generated by NMDA receptor activation, resulting in spectrin and PHLPP1β (SCOP) degradation. Rapid calpain-1 activation triggers a number of different signaling pathways, including cytoskeleton reorganization due to spectrin and RhoA truncation, and the ERK pathway through PHLPP1β degradation. In the following minutes, calpain-2 is in turn phosphorylated and stimulated through BDNF-mediated ERK activation; this leads to PTEN degradation, mTOR activation and stimulation of the synthesis of a number of proteins with mRNAs located in dendrites, including PHLPP1β and RhoA. Restoration of normal PHLPP1β levels inhibits ERK, thereby terminating the induction process for LTP.

Figure 2. Opposite functions of calpain-1&2 in neurodegeneration

Stimulation of synaptic NMDAr activates calpain-1, which cleaves PHLPP1, resulting in phosphorylation/activation of Akt and ERK, two pro-survival pathways. Stimulation of extrasynaptic NMDAr activates calpain-2, which cleaves and inactivates STEP, resulting in p38 stimulation and neurodegeneration. Calpains also cleave and activates GSKβ, which phosphorylates tau and results in tauopathy. In addition, calpains cleave p35 into the more active p25 activator of cdk5, which also phosphorylates tau. It is not currently known which calpain is involved in GSK3β and p35 truncation.