Heart failure and the ryanodine receptor: does Occam's razor rule?

Abstract

In heart failure, the amplitude and rate of decay of both contraction and the underlying systolic Ca2+ transient are reduced. A current debate concerns the mechanism of these alterations of calcium handling. One theory invokes decreased activity of the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA)1 while another focuses on alterations in the SR Ca2+ release channel (ryanodine receptor, RyR).2 A significant contribution to this debate is made by Jiang et al3 in this issue of Circulation Research . Calcium that activates contraction comes from two sources: (1) the extracellular fluid, largely via the L-type Ca2+ current ( I Ca); and (2) the SR, by release through the RyR. Because the latter is generally larger and the amplitude of I Ca is not consistently altered in failure (see review4), work has focused on release from the SR. Release occurs via calcium-induced calcium release (CICR) whereby Ca2+ entry increases the probability of opening of a closely apposed RyR (see general reviews5,6⇓). Relaxation requires that [Ca2+]i be lowered by the combined effects of SERCA and Na+-Ca2+ exchange (NCX). The activity of SERCA is depressed by the accessory protein phospholamban and this inhibition is removed by phosphorylation, providing a mechanism whereby sympathetic stimulation can increase SR Ca2+ content and hence Ca2+ release from the SR. Importantly, depression of SERCA activity will not only decrease the amplitude of the Ca2+ transient (by decreasing SR content) but will also directly slow the rate of decay. The RyR can be phosphorylated,7 and there is an important interaction between an auxiliary protein (FKBP), phosphorylation, and RyR opening. Briefly, FKBP stabilizes interactions between RyRs such that …