Potassium chloride (KCl)-depolarization has been used to study the properties of L-type Ca2+ channel-mediated signal transduction in hippocampal neurons. Calcium influx through L-type Ca2+ channels stimulates a second messenger pathway that transactivates genes under the regulatory control of the Ca2+-and cyclic AMP-responsive element (CRE). Here, we show that in striatal neurons, but not in hippocampal neurons, CRE binding protein (CREB) phosphorylation and CRE-mediated gene expression after KCl-depolarization depends on functional NMDA receptors. This difference in NMDA receptor dependence is not due to different properties of L-type Ca2+ channels in either neuronal type, but rather to different neuron-intrinsic properties. Despite this variation, the second messenger pathway activated by KCl requires Ca2+/calmodulin (CaM) kinase for CREB phosphorylation in both neuronal types. We conclude that depolarization by KCl works differently in striatal and hippocampal neurons.