An increase in Ca²⁺ influx through L-type Ca²⁺ channels is thought to contribute to neuronal dysfunctions that underlie senile symptoms and Alzheimer's disease. The molecular basis of the age-dependent up-regulation in neuronal L-type Ca²⁺ channel activity is largely unknown. We show that phosphorylation of the L-type channel Ca_v1.2 by cAMP-dependent protein kinase is increased >2-fold in the hippocampus of aged rats. The hippocampus is critical for learning and is one of the first brain regions to be affected in Alzheimer's disease. Phosphorylation of Ca_v1.2 by cAMP-dependent protein kinase strongly enhances its activity. Therefore, increased Ca_v1.2 phosphorylation may account for a substantial portion of the age-related rise in neuronal Ca²⁺ influx and its neuropathological consequences.