Calpain-2 catalytic subunit (CAPN2) (CAPN2)

Calpain-2 catalytic subunit (CAPN2), also known as m-calpain, is a calcium-dependent cysteine protease that plays a critical role in platelet function by cleaving cytoskeletal proteins such as Talin-1 (UniProt: P17655). In platelets, the Calpain-2/Talin-1 axis is essential for "outside-in" signaling through the integrin alphaIIbbeta3 receptor, which facilitates cytoskeletal remodeling, platelet spreading, and stable thrombus formation (PubMed: 22493134). Dysregulation of this pathway is implicated in thrombotic disorders and cardiovascular diseases, making Calpain-2 an attractive target for anti-platelet therapy (PubMed: 28450358). Pharmacological inhibition of Calpain-2 prevents the degradation of Talin-1, leading to reduced platelet aggregation and clot retraction without necessarily abolishing initial adhesion (PubMed: 15611080). This mechanism is distinct from traditional anti-platelet agents that target surface receptors or cyclooxygenase enzymes. However, the high degree of homology between Calpain isoforms, particularly Calpain-1 and Calpain-2, presents significant challenges for achieving therapeutic selectivity. Furthermore, the broad tissue distribution of Calpain-2 raises concerns regarding systemic toxicity and off-target effects in non-hematological tissues. Current research focuses on developing small-molecule inhibitors that can selectively target the platelet-specific functions of Calpain-2 to treat conditions like myocardial infarction and stroke.

Other names

m-calpainCANP2Calpain-2Calcium-activated neutral proteinase 2CANP 2

Inhibition of Calpain-2 proteolytic activity to prevent Talin-1 cleavage and subsequent cytoskeletal remodeling.