β-Subunit of the voltage-gated Ca2+ channel Cav1.2 drives signaling to the nucleus via H-Ras

Proceedings of the National Academy of Sciences of the United States of America
Evrim ServiliDaphne Atlas

Abstract

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 α11.2W440A/β2b/α2δ, a mutation that disrupts the interaction between α11.2 and β2 subunits. Pulldown assays in neuronal SH-SY5Y cells and in vitro binding of recombinant H-Ras and β2 confirmed the importance of the intracellular β2 subunit for depolarization-induced gene activation. Using a Ca2+-impermeable mutant channel α11.2L745P/β2b/α2δ or disrupting Ca2+/calmodulin binding to the channel using the channel mutant α11.2I1624A/β2b/α2δ, we demonstrate that depolarization-induced c-Fos and MeCP2 activation does not depend on Ca2+ transport by the channel. Thus, in contrast to the paradigm that elevated intracellular Ca2+ drives nuclear...Continue Reading

References

Aug 7, 1986·Nature·J I Morgan, T Curran
Jun 15, 1995·The Journal of Physiology·M De Waard, K P Campbell
Dec 10, 2002·Annual Review of Physiology·William A Sather, Edwin W McCleskey
Jul 10, 2003·Current Opinion in Neurobiology·Karl DeisserothRichard W Tsien
Jun 24, 2004·Acta Crystallographica. Section D, Biological Crystallography·Yarden OpatowskyJoel A Hirsch
Sep 16, 2004·Science's STKE : Signal Transduction Knowledge Environment·John Colicelli
Feb 25, 2005·The Journal of Biological Chemistry·Brian S FinlinDouglas A Andres
Sep 15, 2005·The Journal of Biological Chemistry·Annette HohausSteffen Hering
Nov 16, 2005·Proceedings of the National Academy of Sciences of the United States of America·Johann SchredelsekerManfred Grabner
Jun 23, 2006·The Journal of Biological Chemistry·Brian S FinlinDouglas A Andres
Feb 22, 2007·Nature Reviews. Neuroscience·Robert D Burgoyne
May 3, 2007·PLoS Biology·Steve W LocklessRoderick MacKinnon
Sep 27, 2008·Neuron·Gary A WaymanThomas R Soderling
Dec 9, 2008·Biochemistry·Yamit HagaliliDaphne Atlas
Apr 16, 2010·Nature·Tae-Kyung KimMichael E Greenberg
Oct 19, 2010·Channels·Robyn Flynn, Gerald W Zamponi
May 11, 2011·Cold Spring Harbor Perspectives in Biology·Anne E West, Michael E Greenberg
Jul 23, 2011·Genes & Cancer·Larry A Feig

❮ Previous
Next ❯

Citations

Jul 6, 2020·Pflügers Archiv : European journal of physiology·Andrea MarcantoniEmilio Carbone
Nov 17, 2020·Frontiers in Cell and Developmental Biology·Ya'nan LiFeng Lan
Apr 24, 2021·Traffic·Rachel ConradPatricia Hidalgo

❮ Previous
Next ❯

Related Concepts

Related Feeds

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.