This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Eisner, D.A. Articles by Trafford, A.W. Search for Related Content PubMed PubMed Citation Articles by Eisner, D.A. Articles by Trafford, A.W. Related Collections Animal models of human disease Calcium cycling/excitation-contraction coupling Heart failure - basic studies Ion channels/membrane transport

(Circulation Research. 2002;91:979.)
© 2002 American Heart Association, Inc.

Editorials

Heart Failure and the Ryanodine Receptor

Does Occam’s Razor Rule?

D.A. Eisner, A.W. Trafford

From the Unit of Cardiac Physiology, Manchester University, Manchester, UK.

Correspondence to D.A. Eisner, Unit of Cardiac Physiology, 1.524 Stopford Bldg, Manchester University, Oxford Rd, Manchester M13 9PT, UK. E-mail eisner@man.ac.uk

Key Words: heart failure • SERCA • hyperphosphorylation

An extract of the first 250 words of the full text is provided, because this article has no 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.

Excitation-Contraction Coupling

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 reviews^5,6). 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.

Phosphorylation of the RyR

The RyR can be phosphorylated,⁷ and there is . . . [Full Text of this Article]

This article has been cited by other articles:

				L. M. Blayney, J.-L. Jones, J. Griffiths, and F. A. Lai A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201 Cardiovasc Res, September 2, 2009; (2009) cvp273v2. [Abstract] [Full Text] [PDF]

				X. H. T. Wehrens, S. E. Lehnart, S. Reiken, R. van der Nagel, R. Morales, J. Sun, Z. Cheng, S.-X. Deng, L. J. de Windt, D. W. Landry, et al. Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure PNAS, July 5, 2005; 102(27): 9607 - 9612. [Abstract] [Full Text] [PDF]

				M. J. Lohse, S. Engelhardt, and T. Eschenhagen What Is the Role of {beta}-Adrenergic Signaling in Heart Failure? Circ. Res., November 14, 2003; 93(10): 896 - 906. [Abstract] [Full Text] [PDF]

				D. M. Bers, D. A. Eisner, and H. H. Valdivia Sarcoplasmic Reticulum Ca2+ and Heart Failure: Roles of Diastolic Leak and Ca2+ Transport Circ. Res., September 19, 2003; 93(6): 487 - 490. [Full Text] [PDF]

				S. A. Khan, M. W. Skaf, R. W. Harrison, K. Lee, K. M. Minhas, A. Kumar, M. Fradley, A. A. Shoukas, D. E. Berkowitz, and J. M. Hare Nitric Oxide Regulation of Myocardial Contractility and Calcium Cycling: Independent Impact of Neuronal and Endothelial Nitric Oxide Synthases Circ. Res., June 27, 2003; 92(12): 1322 - 1329. [Abstract] [Full Text] [PDF]

				F. Brette and C. Orchard T-Tubule Function in Mammalian Cardiac Myocytes Circ. Res., June 13, 2003; 92(11): 1182 - 1192. [Abstract] [Full Text] [PDF]

				A. R. Marks A Guide for the Perplexed: Towards an Understanding of the Molecular Basis of Heart Failure Circulation, March 25, 2003; 107(11): 1456 - 1459. [Full Text] [PDF]