biostudies-literatureUnknown115(37)Servili EDepolarization-induced signaling to the nucleus by the L-type voltage-gated calcium channel Cav1.2 is widely assumed to proceed by elevating intracellular calcium. The apparent lack of quantitative correlation between Ca²⁺ influx and gene activation suggests an alternative activation pathway. Here, we demonstrate that membrane depolarization of HEK293 cells transfected with α₁1.2/β2b/α2δ subunits (Cav1.2) triggers c-Fos and MeCP2 activation via the Ras/ERK/CREB pathway. Nuclear signaling is lost either by absence of the intracellular β2 subunit or by transfecting the cells with the channel mutant α₁1.2^W440A/β2b/α2δ, a mutation that disrupts the interaction between α₁1.2 and β2 subunits. Pulldown assays in neuronal SH-SY5Y cells and in Proceedings of the National Academy of Sciences of the United States of AmericaE8624-E8633https://www.ebi.ac.uk/biostudies/studies/S-EPMC6140482biostudies-literatureβ-Subunit of the voltage-gated Ca²⁺ channel Cav1.2 drives signaling to the nucleus via H-Ras.PMC6140482Servili EAtlas DTrus MMaayan Dfalseβ-Subunit of the voltage-gated Ca²⁺ channel Cav1.2 drives signaling to the nucleus via H-Ras.Depolarization-induced signaling to the nucleus by the L-type voltage-gated calcium channel Cav1.2 is widely assumed to proceed by elevating intracellular calcium. The apparent lack of quantitative correlation between Ca²⁺ influx and gene activation suggests an alternative activation pathway. Here, we demonstrate that membrane depolarization of HEK293 cells transfected with α₁1.2/β2b/α2δ subunits (Cav1.2) triggers c-Fos and MeCP2 activation via the Ras/ERK/CREB pathway. Nuclear signaling is lost either by absence of the intracellular β2 subunit or by transfecting the cells with the channel mutant α₁1.2^W440A/β2b/α2δ, a mutation that disrupts the interaction between α₁1.2 and β2 subunits. Pulldown assays in neuronal SH-SY5Y cells and in 2018-01-01T00:00:00Z2018 Sep2026-06-08T04:21:23.4Z2019-08-04T07:25:53ZS-EPMC61404823015036910.1073/pnas.1805380115