Mini-review: "Hippocalcin: Molecular mechanisms and therapeutic potential in neuronal function"

Hippocalcin (HPCA), a neuronal Ca²⁺ sensor protein in the EF-hand superfamily, plays a key role in calcium signaling and neurological function in the central nervous system. This review highlights HPCA's structure-function relationships and clinical significance. Through Ca2⁺-dependent conformational changes and a unique calcium-myristoyl switch, HPCA dynamically associates with membranes, acting as both sensor and effector. It modulates neuronal excitability, synaptic plasticity, neurodevelopment, and neuroprotection. Notably, HPCA is critical in mediating slow afterhyperpolarization, a key mechanism for adjusting neuronal firing patterns and maintaining excitability homeostasis. It also influences neural stem cell fate by promoting neuronal differentiation and suppressing astrocytic differentiation. HPCA maintains mitochondrial calcium homeostasis and activates survival pathways, protecting against apoptosis and oxidative stress. Its dysregulation is implicated in Alzheimer's and Parkinson's diseases, epilepsy, depression, schizophrenia, and dystonia. Given its restricted expression in the brain and multifaceted functional roles, further elucidation of HPCA-mediated signaling mechanisms is warranted to advance the development of targeted therapeutic strategies for a broad spectrum of neurological disorders.