The L-type voltage-gated calcium channel Cav1.2 activates signaling cascades that regulate neuronal-specific transcription factors such as CREB and immediate-early genes. The general dogma says that Cav1.2 activates the downstream signaling strictly via intracellular calcium increase.
In our paper, we show that the interaction of the intracellular β-subunit of the channel with H-Ras is responsible for gene activation triggered by membrane depolarization. Moreover, we show that gene transcription requires the binding of Ca2+ ions to the channel pore but is calcium-influx independent. These results show a cascade of protein-protein interactions between the channel and H-Ras linking membrane depolarization to rapid induction of gene transcription via the ERK-CREB pathway.
As the mutations in the signaling pathway regulated L-type voltage-gated Ca2+ channels have been shown to be responsible for neurodevelopmental disorders such as autism, understanding this mechanism can help us to treat these diseases.