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The fight-or-flight response of the heart reloaded

Commented by Wolfgang A. Linke

Signal Transduction, Mechano-Transduction
Ion Channels, Electrophysiology

The activity of voltage-gated calcium channels in myocardium (CaV1.2 ) increases during the fight-or-flight response.1 If CaV1.2 channel opening is boosted, this results in a stronger and faster heartbeat. Protein kinase (PK)A is known to modulate channel opening by phosphorylating amino-acid residues in the channel.2 In a new paper reported in Nature, Liu et al. engineered the channel in such a way that all candidate phosphorylation sites were converted to non-phosphorylatable alanine. Surprisingly, PKA-mediated enhancement of these mutated L-type channels persisted. The authors therefore engineered channel subunits linked to an enzyme that adds biotin to any protein within a 20 nm radius and identified tagged proteins by mass spectrometry—an approach called proximity proteomics.3 Through a series of elegant experiments, they showed that the calcium-channel inhibitor Rad,4 a monomeric G protein, is enriched in the CaV1.2 microenvironment but is depleted during β-adrenergic stimulation. Phosphorylation by PKA of specific serine residues on Rad decreased its affinity for β subunits and relieved constitutive inhibition of CaV1.2, observed as an increase in channel open probability. With their findings, the authors extend our view on how the b-adrenergic signaling cascade works. Accordingly, adrenaline binds and activates the β-adrenergic receptor, which activates cAMP-producing adenylyl cyclase, resulting in PKA activation. PKA then phosphorylates Rad and causes it to leave the vicinity of the calcium channel, thereby preventing it from inhibiting the channel. Thus, Rad and other members of this family of proteins could be central players in calcium-channel modulation. Whether cardiac regulation by Rad is of clinical value needs to be studied in future work.  However, the heart’s functional reserve may depend, in part, on Rad, thus raising the possibility that pathway alterations are involved in heart failure, when the functional reserve is reduced.


  1. Hartzell HC, Méry PF, Fischmeister R, Szabo G. Sympathetic regulation of cardiac calcium current is due exclusively to cAMP-dependent phosphorylation. Nature. 1991; 351: 573–6.
  2. Bünemann M, Gerhardstein BL, Gao T, Hosey MM. Functional regulation of L-type calcium channels via protein kinase A-mediated phosphorylation of the beta(2) subunit. J Biol Chem. 1999 Nov 26;274(48):33851-4.
  3. Rhee HW, Zou P, Udeshi ND, Martell JD, Mootha VK, Carr SA, Ting AY. Proteomic mapping of mitochondria in living cells via spatially restricted enzymatic tagging. Science. 2013 Mar 15;339(6125):1328-1331. doi: 10.1126/science.1230593.
  4. Finlin BS, Crump SM, Satin J, Andres DA. Regulation of voltage-gated calcium channel activity by the Rem and Rad GTPases. Proc Natl Acad Sci USA. 2003 Nov 25;100(24):14469-74.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.