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 D 1 -like dopamine receptors D 1 and D 5 . Here, we found that the L-type Ca 2+ channel Ca V 1.2 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 V 1.2 in the soma and Ca 2+ influx in the dendrites. This effect was mediated through the second messenger cAMP and cAMP-dependent protein kinase (PKA), which phosphorylated the Ca V 1.2 α 1 subunit at Ser 1928 . Ca V 1.2 and D 5 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 V 1.2 α 1 S1928A knockin animals. These findings identify Ca V 1.2 as a key D 1/5 signaling effector that supports dopamine-driven executive functions in cognition.