Editors' ChoiceCalcium Channels

Heart Failure and Hyperphosphorylation

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Science's STKE  16 May 2000:
Vol. 2000, Issue 32, pp. tw1
DOI: 10.1126/stke.2000.32.tw1

The ryanodine receptor 2 (RyR2) provides the major source of calcium for excitation-contraction coupling in the heart. This receptor consists of four RyR2 subunits and four FKBP12.6 subunits. Marx et al. show that the RyR2 subunits are phosphorylated in vitro and in vivo by protein kinase A (PKA), which leads to dissociation of the FKBP12.6 subunits, which results in alterations in the electrophysiological properties of these calcium-release channels. Furthermore, the same altered biophysical properties occur in cardiac heart failure and are associated with hyperphosphorylation of the RyRs and decreased association with the regulatory subunit FKBP12.6. The authors demonstrate that the RyRs are in a large macromolecular complex that includes the RyR, FKBP12.6, PKA, protein phosphatases (PPA and PP2A), and the anchoring protein mAKAP. The mechanism described for physiological regulation of the RyR2 by PKA-controlled FKBP12.6 binding and the discovery of PKA-hyperphosphorylated RyRs in cardiac heart failure patients has important implications for using drugs that alter β-adrenergic receptor signaling in the treatment of this life-threatening disease.

Marx, S.O., Reiken, S., Hisamatsu, Y., Jayaraman, T., Burkhoff, D., Rosemblit, N., and Marks, A.R. (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): Defective regulation in failing hearts. Cell 101: 365-376. [Online Journal]

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