Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


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


Molecular Mechanism of Calcium Channel Regulation in the Fight-or-Flight Response

Matthew D. Fuller1, Michelle A. Emrick1*, Martin Sadilek2, Todd Scheuer1, and William A. Catterall1{dagger}

1 Department of Pharmacology, University of Washington, Box 357280, Seattle, WA 98195–7280, USA.
2 Department of Chemistry, Box 351700, University of Washington, Seattle, WA 98195–1700, USA.

* Present address: VLST Corporation, 307 Westlake Avenue North, Seattle, WA 98109, USA.

Abstract: During the fight-or-flight response, the sympathetic nervous system stimulates L-type calcium ion (Ca2+) currents conducted by CaV1 channels through activation of β-adrenergic receptors, adenylyl cyclase, and phosphorylation by adenosine 3',5'-monophosphate–dependent protein kinase [also known as protein kinase A (PKA)], increasing contractility of skeletal and cardiac muscles. We reconstituted this regulation of cardiac CaV1.2 channels in non-muscle cells by forming an autoinhibitory signaling complex composed of CaV1.2{Delta}1800 (a form of the channel truncated at the in vivo site of proteolytic processing), its noncovalently associated distal carboxyl-terminal domain, the auxiliary {alpha}2{delta}1 and β2b subunits, and A-kinase anchoring protein 15 (AKAP15). A factor of 3.6 range of CaV1.2 channel activity was observed from a minimum in the presence of protein kinase inhibitors to a maximum upon activation of adenylyl cyclase. Basal CaV1.2 channel activity in unstimulated cells was regulated by phosphorylation of serine-1700 and threonine-1704, two residues located at the interface between the distal and the proximal carboxyl-terminal regulatory domains, whereas further stimulation of channel activity through the PKA signaling pathway only required phosphorylation of serine-1700. Our results define a conceptual framework for CaV1.2 channel regulation and identify sites of phosphorylation that regulate channel activity.

{dagger} To whom correspondence should be addressed. E-mail: wcatt{at}

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 »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882