Caspases in synaptic plasticity

Caspases are a family of cysteine proteases that have a conserved cysteine residue at their active site and cleave after an aspartate residue in their substrates. As key proteolytic enzymes involved in programmed cell death (or apoptosis), caspases are found in a wide range of animals from worms to humans; in mammals, 12 caspases have been identified. Caspases are generally translated as inactive zymogens and activated through proteolytic cleavage. Based on their structure and function, caspases are classified into two groups: initiator caspases and effector caspases. Initiator caspases (caspase-1, -2, -4, -5, -8, -9, -10, -11 and -12) have a long N-terminal prodomain through which they are recruited to specific protein complexes for activation. Once activated, initiator caspases can cleave and activate downstream effector caspases (e.g. caspase-3, -6, -7, -14), which then go on to proteolyze further cellular substrates, of which many examples are now known [1].Since the discovery of the critical function of the C. elegans caspase ced-3 in programmed cell death [2,3], most members of the caspase family have been demonstrated to be components of apoptotic signaling pathways. The biochemistry and function of these proteases have been predominantly studied in the context of apoptosis. In cells undergoing apoptosis, caspases are activated by two main pathways: the extrinsic pathway and the intrinsic pathway (see Figure 1). The extrinsic pathway is initiated by binding of specific ligands (e.g. tumor necrosis factor alpha [TNFα], Fas ligand, Nerve growth factor [NGF]) to cell surface "death receptors", such as tumor necrosis factor receptor 1 (TNFR1), Fas and nerve growth factor receptor p75NTR [4]. Upon ligand binding, the death receptors multimerize and recruit multiple adaptor molecules to form the death-inducing signaling complex (DISC), which in turn interacts with and activates the initiator caspases [1]. For TNFR1, TNF receptor associated-protein with death domain