Calpain

Calpain is a family of protease enzymes found in almost all eukaryotes and is involved in a variety of cellular processes including cell cycle regulation, cell motility, and apoptosis. Calpains are calcium-dependent, non-lysosomal cysteine proteases that require calcium ions to trigger their proteolytic activity. The calpain system has been implicated in pathological conditions such as neurodegenerative diseases, muscular dystrophies, cancer, and ischemia.

Structure and Function

Calpains are heterodimers consisting of a large catalytic subunit and a smaller regulatory subunit. The catalytic subunit is encoded by the CAPN1 gene for μ-calpain and CAPN2 for m-calpain, which are the two most well-studied members of this family. The regulatory subunit, common to both μ-calpain and m-calpain, is encoded by the CAPNS1 gene. This subunit is essential for the stability and activity of the calpain enzyme.

The activity of calpain is regulated by calcium concentration within the cell. At low calcium levels, calpains remain inactive. However, upon an increase in intracellular calcium, calpains undergo a conformational change that allows them to cleave their substrates. This calcium-dependent activation is crucial for the involvement of calpains in calcium-regulated processes.

Biological Roles

Calpains play significant roles in various cellular functions, including:

• Cytoskeleton remodeling: Calpains modulate the dynamics of the cytoskeleton by cleaving cytoskeletal proteins, which is essential for cell migration and cell division.
• Signal transduction: By cleaving various substrates, calpains participate in the regulation of signal transduction pathways that control cell proliferation, differentiation, and apoptosis.
• Neuronal function: In neurons, calpains are involved in axonal degeneration and synaptic plasticity, processes critical for learning and memory.
• Cell death: Calpains can initiate or execute apoptosis by cleaving key cellular proteins, including caspases and cytoskeletal proteins.

Pathological Implications

Dysregulation of calpain activity is associated with several diseases:

• Neurodegenerative diseases: Abnormal calpain activity is observed in conditions such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, where it contributes to neuronal death and disease progression.
• Muscular dystrophies: Mutations in calpain 3 (CAPN3) lead to a form of muscular dystrophy known as Limb-girdle muscular dystrophy type 2A (LGMD2A), characterized by progressive muscle weakness.
• Cancer: Overexpression of calpains has been linked to tumor progression, invasion, and metastasis in various cancers.
• Ischemia: During ischemic injury, such as in myocardial infarction or stroke, elevated intracellular calcium levels activate calpains, leading to tissue damage and cell death.

Research and Therapeutic Potential

Given their involvement in numerous pathological conditions, calpains represent potential targets for therapeutic intervention. Inhibitors of calpain have shown promise in preclinical models of neurodegeneration, cardiovascular diseases, and cancer. However, the development of specific, potent, and clinically viable calpain inhibitors remains a challenge.

See Also

• Protease
• Calcium signaling
• Apoptosis
• Neurodegeneration
• Muscular dystrophy