calpains

Calpains are a family of calcium-dependent cysteine proteases found in many tissues across eukaryotes. They typically function as heterodimers composed of a large catalytic subunit (such as μ-calpain, calpain-1; or m-calpain, calpain-2) and a common small regulatory subunit (CAPNS1). Activation requires binding of calcium, with different isoforms responding to distinct calcium concentrations. Activity is tightly regulated by endogenous inhibitors, notably calpastatin, which binds to the catalytic subunits to prevent proteolysis.

Calpains cleave a variety of cellular substrates, contributing to controlled proteolysis during processes such as cytoskeletal remodeling, cell motility, and signaling. Common substrates include cytoskeletal proteins like spectrin and ankyrin, as well as components of focal adhesions such as talin and vinculin. Calpain-3 (encoded by CAPN3) is a muscle-specific isoform implicated in sarcomere maintenance and muscle remodeling, highlighting the tissue-specific roles of the family.

Genetics and diversity: in humans, CAPN1 and CAPN2 encode the ubiquitous large subunits for μ- and m-calpain, respectively, and CAPNS1 encodes the regulatory subunit. Other family members, including CAPN3 and additional CAPN genes, provide tissue-specific calpain functions. Regulation by calpastatin (CAST) adds another layer of control over proteolytic activity.

Physiological and pathological relevance: calpains participate in normal cellular turnover and signaling, but their dysregulation is linked to pathology. Excessive calpain activation is associated with excitotoxicity and ischemic injury in the nervous system, neurodegenerative diseases, muscular dystrophy, and cataracts. Consequently, calpains are studied as potential therapeutic targets, with inhibitors explored in preclinical contexts, though clinical translation is constrained by the enzymes’ broad roles in physiology.