Calpain 1 and Calpain 2 (CAPN1 and CAPN2)

Calpain-1 and Calpain-2 are the two best-studied isoforms of the calpain family, both functioning as calcium-dependent, non-lysosomal cysteine proteases[6][5]. Each is a heterodimer: the 80-kDa large catalytic subunit is encoded by either CAPN1 (calpain-1/μ-calpain) or CAPN2 (calpain-2/m-calpain), and both share a common 28-kDa small regulatory subunit (CAPNS1). They act primarily as limited proteases, cleaving many intracellular substrates to modify their activity, and thereby regulate cell signaling, adhesion, migration, synaptic plasticity, apoptosis, and proliferation[5][3][6][1]. Calpain-1 tends to support neuroprotective signaling and plasticity, while calpain-2 can promote neurodegeneration under excitotoxic conditions[3]. Both isoforms have distinct activation thresholds for calcium, structural features, and substrate profiles. Their abnormal activation or inhibition has critical roles in cancer, neurodegenerative disease, inflammation, and pathology related to cell migration and death, making them attractive but challenging targets for drug development[4][5][3][6].

Other names

μ-calpain (Calpain-1)m-calpain (Calpain-2)CANP1 (Calpain-1)CANP2 (Calpain-2)CAPN1 and CAPN2 (gene/protein names)Large subunit (80 kDa, CAPN1 or CAPN2)Small regulatory subunit CAPNS1 (shared by both isoforms)

Active site inhibition (experimental compounds); Allosteric inhibition (targeting heterodimerization of catalytic/regulatory subunits); Modulation of calcium-binding and enzyme activation