This paper  extends previous studies demonstrating a key role of voltage-gated L-type Ca2+ channels in the modulation of activity-dependent gene transcription. Earlier work in cultured neurons had already shown that L-type channel activity is required to activate gene expression through different signaling pathways, including the Ras/MAPK pathway [2-4]. This is confirmed in the present study (primarily in experiments with HEK-293 cells) but there are important differences in the way nuclear signaling gets activated. In contrast to previous models , it is shown that the Ras/MAPK pathway is turned on by a direct physical interaction of the L-type channel (only Cav1.2 was studied) with Ras through the channel’s beta-subunit. Moreover, this interaction requires binding of extracellular Ca2+ to the pore-forming alpha1-subunit but no Ca2+ influx through the channel. Also no binding of calmodulin to the channel is required. This strongly suggests a direct conformational coupling of Cav1.2 to Ras activation and adds to other evidence of conformational coupling of L-type Ca2+ channels [5-6]. However, further experiments are required to demonstrate that this mechanism also exists in neurons.
Comments by Jörg Striessnig, University of Innsbruck
(1) Servili E et al. (2018). β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras. Proc Natl Acad Sci USA, 115(37):E8624-E8633. doi: 10.1073/pnas.1805380115. [PMID: 30150369]
(2) Dolmetsch RE et al. (2001). Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway. Science, 294(5541):333-9. [PMID: 11598293]
(3) Wu GY et al. (2018). Activity-dependent CREB phosphorylation: convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway. Cold Spring Harbor Perspect Biol, 98(5):2808-13. [PMID: 11226322]
(4) Hagenston AM & Bading H (2018). Calcium signaling in synapse-to-nucleus communication. Mol Pharmacol, 3(11):a004564. doi: 10.1101/cshperspect.a004564. [Epub ahead of print]. [PMID: 30021858]
(5) Krey JF et al. (2013). Timothy syndrome is associated with activity-dependent dendritic retraction in rodent and human neurons. Nat Neurosci 16:201-9. [PMID: 23313911]
(6) Li B et al. (2016). Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression. Science 351:863-7. [PMID: 26912895]