Calpain (Calcium-dependent cysteine protease) (CAPN)

Calpains are a conserved family of calcium-dependent, non-lysosomal cysteine proteases that play a critical role in cellular signaling by performing limited proteolysis on specific substrates. The most prominent members, Calpain-1 (mu-calpain) and Calpain-2 (m-calpain), regulate diverse processes including cytoskeletal remodeling, cell motility, and apoptosis by cleaving proteins such as spectrin, talin, and various transcription factors (UniProt: P07384, P17655). Under pathological conditions involving calcium dyshomeostasis, such as stroke, traumatic brain injury, and Alzheimer's disease, calpains become hyperactivated, leading to the excessive and irreversible degradation of cellular substrates and subsequent cell death (PubMed: 25103275). Therapeutic strategies focus on the development of calpain inhibitors to prevent this damage; however, the term "Cellular calpain substrates" refers to the downstream proteins being cleaved rather than the therapeutic target itself, which is the calpain enzyme. Achieving isoform selectivity and avoiding the inhibition of related proteases like cathepsins remains a significant challenge in the clinical development of these inhibitors (PubMed: 30245124). Monitoring the breakdown products of specific substrates, such as alpha-II spectrin, serves as a critical biomarker for assessing calpain activity and the efficacy of potential inhibitors in clinical and preclinical settings (PubMed: 18463347).

Other names

Calcium-activated neutral proteaseCANPCalpain familyMicromolar calpainMillimolar calpainCalpain substrates

Inhibition of the catalytic activity of calpain enzymes to prevent the pathological over-degradation of vital cellular substrates.