Voltage-gated Ca2+ channels (VGCCs) are membrane proteins that determine the activity and survival of neurons, and mutations in the
P/Q-type VGCCs are known to cause cerebellar ataxia. VGCC dysfunction may also underlie acquired peripheral and central nervous system
diseases associated with small-cell lung cancer, including Lambert–Eaton myasthenic syndrome (LEMS) and paraneoplastic cerebellar ataxia
(PCA). The pathogenic role of anti-VGCC antibody in LEMS is well established. Although anti-VGCC antibody is also found in a significant
fraction of PCA patients, its contribution to PCA is unclear. Using a polyclonal peptide antibody against a major immunogenic region in
P/Q-type VGCCs (the extracellular Domain-III S5–S6 loop), we demonstrated that such antibody was sufficient to inhibit VGCC function in
neuronal and recombinant VGCCs, alter cerebellar synaptic transmission, and confer the phenotype of cerebellar ataxia. Our data support the
hypothesis that anti-VGCC antibody may play a significant role in the pathogenesis of cerebellar dysfunction in PCA.