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

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Science Signaling  28 Sep 2010:
Vol. 3, Issue 141, pp. ra70
DOI: 10.1126/scisignal.2001152

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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.

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