Counterintuitive Therapy

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Science  26 May 2000:
Vol. 288, Issue 5470, pp. 1303
DOI: 10.1126/science.288.5470.1303c

Stress releases adrenaline, which stimulates heart muscle, which contracts more vigorously. Why, then, are β-blockers (inhibitors of the β-adrenergic signaling pathway) used to treat heart failure?

Marx et al. provide an answer by showing that the calcium release channel (also known as the ryanodine receptor) of the cardiac sarcoplasmic reticulum (SR) is phosphorylated by the cAMP-activated protein kinase, which leads to dissociation of the FKBP12.6 subunits, which results in an increased sensitivity to calcium, which triggers opening of the channel. The SR provides the major source of calcium for excitation-contraction coupling in the heart, and cAMP is produced by the adrenergic pathway. In heart failure patients, however, high steady-state phosphorylation of the channel not only blunts the response to calcium but also limits the capacity of exogenous β-agonists to stimulate heart contraction. The authors suggest that diminished phosphatase activity may exist in the pathologic state and thus that β-blockers may act by throttling back the endogenous protein kinase activity and in this fashion diminish diastolic phosphorylation levels.—NG

Cell101, 365 (2000).

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