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

RESEARCH ARTICLES

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}u.washington.edu

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).

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