Stimulation of Ca ²⁺ channel Ca _V 1.2 activity by dopamine signaling augments spatial working memory

Dopamine drives the neuronal activity and synaptic plasticity required for various forms of learning. It supports short-term working memory through activation of the D₁-like dopamine receptors D₁ and D₅. Here, we found that the L-type Ca²⁺ channel Ca_V1.2 was a critical mediator of D_1/5 signaling in hippocampal pyramidal neurons. In cultured mouse hippocampal neurons, a D_1/5 agonist augmented currents through Ca_V1.2 in the soma and Ca²⁺ influx in the dendrites. This effect was mediated through the second messenger cAMP and cAMP-dependent protein kinase (PKA), which phosphorylated the Ca_V1.2 α₁ subunit at Ser¹⁹²⁸. Ca_V1.2 and D₅ colocalized, suggesting that this signaling was spatially restricted. In mice, D_1/5 agonism facilitated spatial working memory in wild-type but not litter-matched Ca_V1.2 α₁ S1928A knockin animals. These findings identify Ca_V1.2 as a key D_1/5 signaling effector that supports dopamine-driven executive functions in cognition.