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Sci. Signal., 28 September 2010
Vol. 3, Issue 141, p. ra70
[DOI: 10.1126/scisignal.2001152]


Editor's Summary

The Complex Regulation of Heartbeat
The pounding heart associated with moments of intense exercise, stress, or terror depends on activation of the sympathetic nervous system and the consequent increase in calcium influx through cardiac calcium channels. This increase in calcium influx is mediated through stimulation of protein kinase A (PKA) by the β-adrenergic signaling pathway and the ensuing PKA-dependent phosphorylation of the CaV1.2 channel. Fuller et al. reconstituted the CaV1.2 channel signaling complex in non-muscle cells and discovered that PKA-dependent stimulation of channel activity required both the proper ratio of CaV1.2 to the scaffolding protein A-kinase–anchoring protein 15 (AKAP15) and noncovalent association with the distal C-terminal domain of CaV1.2, which is proteolytically processed in vivo. The autoinhibitory effect of noncovalent association of the distal C-terminal domain is relieved by phosphorylation of a serine residue at the interface between the distal and the proximal C-terminal domains, leading to disinhibition of channel activity in the fight-or-flight response.

Citation: M. D. Fuller, M. A. Emrick, M. Sadilek, T. Scheuer, W. A. Catterall, Molecular Mechanism of Calcium Channel Regulation in the Fight-or-Flight Response. Sci. Signal. 3, ra70 (2010).

Read the Full Text

Differential regulation of CaV1.2 channels by cAMP-dependent protein kinase bound to A-kinase anchoring proteins 15 and 79/150.
M. D. Fuller, Y. Fu, T. Scheuer, and W. A. Catterall (2014)
J. Gen. Physiol. 143, 315-324
   Abstract »    Full Text »    PDF »
L-Type CaV1.2 Calcium Channels: From In Vitro Findings to In Vivo Function.
F. Hofmann, V. Flockerzi, S. Kahl, and J. W. Wegener (2014)
Physiol Rev 94, 303-326
   Abstract »    Full Text »    PDF »
Phosphorylation sites required for regulation of cardiac calcium channels in the fight-or-flight response.
Y. Fu, R. E. Westenbroek, T. Scheuer, and W. A. Catterall (2013)
PNAS 110, 19621-19626
   Abstract »    Full Text »    PDF »
Manipulating L-type calcium channels in cardiomyocytes using split-intein protein transsplicing.
P. Subramanyam, D. D. Chang, K. Fang, W. Xie, A. R. Marks, and H. M. Colecraft (2013)
PNAS 110, 15461-15466
   Abstract »    Full Text »    PDF »
{beta}-Adrenergic Regulation of the L-type Ca2+ Channel Does Not Require Phosphorylation of {alpha}1C Ser1700.
L. Yang, A. Katchman, T. Samad, J. P. Morrow, R. L. Weinberg, and S. O. Marx (2013)
Circ. Res. 113, 871-880
   Abstract »    Full Text »    PDF »
Regulation of L-type calcium channel sparklet activity by c-Src and PKC-{alpha}.
J. Gulia, M. F. Navedo, P. Gui, J.-T. Chao, J. L. Mercado, L. F. Santana, and M. J. Davis (2013)
Am J Physiol Cell Physiol 305, C568-C577
   Abstract »    Full Text »    PDF »
Regulation of Cardiac L-Type Ca2+ Channel CaV1.2 Via the {beta}-Adrenergic-cAMP-Protein Kinase A Pathway: Old Dogmas, Advances, and New Uncertainties.
S. Weiss, S. Oz, A. Benmocha, and N. Dascal (2013)
Circ. Res. 113, 617-631
   Abstract »    Full Text »    PDF »
Protein kinase A regulation of T-type Ca2+ channels in rat cerebral arterial smooth muscle.
O. F. Harraz and D. G. Welsh (2013)
J. Cell Sci. 126, 2944-2954
   Abstract »    Full Text »    PDF »
The voltage-dependent L-type Ca2+ (CaV1.2) channel C-terminus fragment is a bi-modal vasodilator.
J. P. Bannister, M. D. Leo, D. Narayanan, W. Jangsangthong, A. Nair, K. W. Evanson, J. Pachuau, K. S. Gabrick, F. A. Boop, and J. H. Jaggar (2013)
J. Physiol. 591, 2987-2998
   Abstract »    Full Text »    PDF »
The cardiac L-type calcium channel distal carboxy terminus autoinhibition is regulated by calcium.
S. M. Crump, D. A. Andres, G. Sievert, and J. Satin (2013)
Am J Physiol Heart Circ Physiol 304, H455-H464
   Abstract »    Full Text »    PDF »
Increased intracellular magnesium attenuates {beta}-adrenergic stimulation of the cardiac CaV1.2 channel.
S. Brunet, T. Scheuer, and W. A. Catterall (2012)
J. Gen. Physiol. 141, 85-94
   Abstract »    Full Text »    PDF »
Cardiomyocytes from AKAP7 knockout mice respond normally to adrenergic stimulation.
B. W. Jones, S. Brunet, M. L. Gilbert, C. B. Nichols, T. Su, R. E. Westenbroek, J. D. Scott, W. A. Catterall, and G. S. McKnight (2012)
PNAS 109, 17099-17104
   Abstract »    Full Text »    PDF »
Ca2+-dependent Transcriptional Control of Ca2+ Homeostasis.
J. R. Naranjo and B. Mellstrom (2012)
J. Biol. Chem. 287, 31674-31680
   Abstract »    Full Text »    PDF »
Anchoring Proteins as Regulators of Signaling Pathways.
A. Perino, A. Ghigo, J. D. Scott, and E. Hirsch (2012)
Circ. Res. 111, 482-492
   Abstract »    Full Text »    PDF »
Deletion of the C-terminal Phosphorylation Sites in the Cardiac {beta}-Subunit Does Not Affect the Basic {beta}-Adrenergic Response of the Heart and the Cav1.2 Channel.
J. Brandmayr, M. Poomvanicha, K. Domes, J. Ding, A. Blaich, J. W. Wegener, S. Moosmang, and F. Hofmann (2012)
J. Biol. Chem. 287, 22584-22592
   Abstract »    Full Text »    PDF »
A-kinase anchoring proteins: scaffolding proteins in the heart.
D. Diviani, K. L. Dodge-Kafka, J. Li, and M. S. Kapiloff (2011)
Am J Physiol Heart Circ Physiol 301, H1742-H1753
   Abstract »    Full Text »    PDF »
Truncation of Murine Cav1.2 at Asp-1904 Results in Heart Failure after Birth.
K. Domes, J. Ding, T. Lemke, A. Blaich, J. W. Wegener, J. Brandmayr, S. Moosmang, and F. Hofmann (2011)
J. Biol. Chem. 286, 33863-33871
   Abstract »    Full Text »    PDF »
Voltage-Gated Calcium Channels.
W. A. Catterall (2011)
Cold Spring Harb Perspect Biol 3, a003947
   Abstract »    Full Text »    PDF »
Deletion of the Distal C Terminus of CaV1.2 Channels Leads to Loss of {beta}-Adrenergic Regulation and Heart Failure in Vivo.
Y. Fu, R. E. Westenbroek, F. H. Yu, J. P. Clark III, M. R. Marshall, T. Scheuer, and W. A. Catterall (2011)
J. Biol. Chem. 286, 12617-12626
   Abstract »    Full Text »    PDF »
Mitochondrial production of reactive oxygen species contributes to the {beta}-adrenergic stimulation of mouse cardiomycytes.
D. C. Andersson, J. Fauconnier, T. Yamada, A. Lacampagne, S.-J. Zhang, A. Katz, and H. Westerblad (2011)
J. Physiol. 589, 1791-1801
   Abstract »    Full Text »    PDF »
{beta}-Adrenergic Regulation of the L-Type Ca2+ Channel CaV1.2 by PKA Rekindles Excitement.
J. W. Hell (2010)
Science Signaling 3, pe33
   Abstract »    Full Text »    PDF »

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